@article {pmid42444499,
year = {2026},
author = {Sellitepe, HE and Aksel, AB and Zıvalı, H and Pehlivanlar Yavrucu, E and Sağlık Özkan, BN and Doğan, İS and Özcan Kosif, K},
title = {Structure-Guided Optimization of 1,2,4-Triazole-Thione-Based Mannich Derivatives as Dual-Target Modulators: AChE/MAO-B.},
journal = {Chemical biology & drug design},
volume = {108},
number = {1},
pages = {e70347},
pmid = {42444499},
issn = {1747-0285},
mesh = {*Triazoles/chemistry/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology/chemical synthesis ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; Molecular Docking Simulation ; *Monoamine Oxidase Inhibitors/chemistry/metabolism/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Alzheimer Disease/drug therapy ; Binding Sites ; },
abstract = {Diseases such as Alzheimer's, Parkinson's, and depression result from neurotransmitter imbalances. In particular, for AD, it is critical to inhibit AChE to preserve the decline in acetylcholine levels and to block excessive MAO-B activity, which leads to nerve damage and cognitive impairment. As current scientific research has moved away from the "one drug for one target" approach toward a "multi-target" strategy, dual-acting inhibitors that simultaneously inhibit both AChE and MAO-B enzymes are considered the most promising new drug candidates for the treatment of Alzheimer's disease. In this study, we investigated the inhibition of AChE, BChE, MAO-A, and MAO-B in the pathophysiology of AD as a working group. Within the scope, 10 new compounds (5a-j) were synthesized, consisting of a phenolic ring, a secondary or tertiary amine tail, and a 1,2,4-triazole core. The cholinesterase and MAO inhibitory profiles of the compounds were investigated using both in vitro and in silico methods. Compound 5b exhibited dual inhibitory activity against AChE and MAO-B enzymes, with IC50 values of 0.136 ± 0.006 μM and 0.108 ± 0.005 μM, respectively. In accordance with 5b, it interacted with crucial amino acids of the hAChE and hMAO-B enzymes in the docking studies. These results suggest that 5b is a dual-target inhibitor of AChE and MAO-B and represents a promising therapeutic option for the treatment of Alzheimer's disease.},
}

*Triazoles/chemistry/metabolism
*Acetylcholinesterase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/metabolism/pharmacology/chemical synthesis
*Monoamine Oxidase/metabolism/chemistry
Humans
Molecular Docking Simulation
*Monoamine Oxidase Inhibitors/chemistry/metabolism/pharmacology
Butyrylcholinesterase/metabolism/chemistry
Structure-Activity Relationship
Animals
Alzheimer Disease/drug therapy
Binding Sites

@article {pmid42444751,
year = {2026},
author = {Zivko, C and Sagar, R and Ahmed, W and Xydia, A and Farinelli, F and Ostlund, I and Das, D and Maher, BJ and Lyketsos, CG and Mahairaki, V},
title = {Heterogeneous responses to memantine in Alzheimer's disease: A precision medicine approach using iPSC models.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70271},
pmid = {42444751},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive and functional decline. Memantine, a commonly prescribed N-methyl-D-aspartate receptor antagonist, appears to slightly delay symptom progression in moderate or advanced stages of AD. Clinical response is highly variable across patients with some benefiting but others not. Induced pluripotent stem cell (iPSC)-derived neurons can provide a donor-dependent model to predict the therapeutic efficacy of memantine.

METHODS: We generated iPSC-derived cortical neurons from 19 individuals (12 AD and 7 cognitively unimpaired [CU]). Assays for calcium influx and oxidative stress were developed and optimized for neurons. Memantine was tested under different treatment conditions. Neurons were exposed to glutamate/glycine to induce calcium influx and menadione to generate oxidative stress. Memantine treatment was applied either acutely (1 hour) or as a 24-hour pre-treatment to evaluate its neuroprotective effects.

RESULTS: Peripheral blood mononuclear cell-derived iPSCs were successfully differentiated into functional neurons, exhibiting comparable electrophysiological properties between AD and CU lines. Calcium influx assays revealed a heterogeneous response among AD and CU neurons, with AD neurons generally displaying higher baseline fluorescence. Memantine treatment for 24 hours significantly reduced calcium influx, with a -9.85% average reduction and a range of -0.39% to -39%. Similarly, reactive oxygen species assays showed menadione-induced oxidative stress was attenuated by 24-hour memantine pre-treatment for a mean -26.05% reduction and a range of -4.23% to -72.21%. The observed variability indicates differential susceptibility to excitotoxicity reduction and or oxidative stress mitigation across lines.

DISCUSSION: This exploratory study establishes a robust in vitro platform to test memantine efficacy using iPSC-derived neurons to model calcium dysregulation and oxidative stress in AD. The observed variability in response highlights the importance of personalized approaches in AD treatment, emphasizing the potential for iPSC-based platforms in precision medicine.},
}

@article {pmid42444752,
year = {2026},
author = {Ding, Z and Gibson, KA and Nascari, DG and Tallant, LE and Bouchal, SM and Dickson, DW and Fryer, JD},
title = {Anti-amyloid nanobody-Fc fusion protein drives potent amyloid clearance through microglial recruitment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70269},
pmid = {42444752},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc-mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid-related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single-domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood-brain barrier (BBB) penetration and allows Fc-mediated functions to be studied independently.

METHODS: We immunized a llama with Aβ aggregates and constructed a phage display library to screen for aggregate-specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre-existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice.

RESULTS: We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind Aβ plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc-less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc-less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10-Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc-mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal.

DISCUSSION: Our findings demonstrate that Fc effector function is indispensable for microglial-mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next-generation immunotherapies. Furthermore, 2D10-Fc represents a promising therapeutic candidate, combining the high-affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.},
}

@article {pmid42445718,
year = {2026},
author = {Kang, L and Salas-Hernandez, JL and Xu, R},
title = {Central neural circuits and their associated mechanisms of inter-organ crosstalk.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1830768},
pmid = {42445718},
issn = {2296-634X},
abstract = {The central nervous system (CNS), which comprises the brain and spinal cord, serves as the core regulatory hub for maintaining homeostasis and coordinating diverse physiological functions. These functions include interoception, cognition, and social behavior. The intricate architecture and extensive connectivity of the CNS enable integration of multi-system responses, thereby ensuring bodily stability and adaptability. The CNS exerts profound regulatory influences on fundamental life-sustaining processes and higher-order cognitive and social functions. This is mediated by distinct neural circuits and molecular mechanisms. CNS dysfunction is strongly associated with the pathogenesis of neurological disorders (Alzheimer's disease, Parkinson's disease, stroke and epilepsy), metabolic diseases (obesity and diabetes), and cardiovascular conditions (hypertension and atherosclerosis). Given the pivotal role of the CNS in both physiological regulation and disease progression, a comprehensive understanding of CNS mechanisms is critical for identifying therapeutic targets. This review systematically examines the regulatory functions of the CNS in physiology and disease. Moreover, this review analyzes the underlying molecular and circuit-level mechanisms, and discusses potential therapeutic strategies. By elucidating the systemic interactions of the CNS, this study aims to highlight its potential as a target for innovative interventions in disease prevention, diagnosis, and treatment.},
}

@article {pmid42445988,
year = {2026},
author = {Delaney, HJ and Islam, S and Healy, D and Oglesby, R and Konda, M and Rietman, GM and Lynch, R and Nazmi, A and Murray, JT and Cunningham, MO and Cunningham, C},
title = {CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag147},
pmid = {42445988},
issn = {1460-2156},
abstract = {Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.},
}

@article {pmid42446837,
year = {2026},
author = {Hsu, CY and Raval, AD and Bainsal, N and Kaur, I and Baig, MR and Turakulov, R and Sapaev, I and Hjazi, A and Alghazali, T and Smerat, A},
title = {Molecular Regulation of Pyroptosis in Alzheimer's Disease: Linking Neuroinflammation, Cell Death, and Therapeutic Targeting.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42446837},
issn = {1559-1182},
mesh = {Humans ; *Pyroptosis/physiology/drug effects ; *Alzheimer Disease/pathology/metabolism/therapy ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism ; *Cell Death/physiology ; *Molecular Targeted Therapy ; Inflammasomes/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound cognitive decline, wherein chronic neuroinflammation plays a pivotal pathogenic role. Central to this inflammatory milieu is pyroptosis, a highly inflammatory form of programmed lytic cell death mediated by gasdermin proteins. This comprehensive review provides an in-depth synthesis of the cellular and molecular mechanisms underlying pyroptosis in AD. We detail the distinct roles of microglia as primary initiators responding to amyloid-beta (Aβ) and tau aggregates, alongside the specific vulnerabilities of neurons facing oxidative stress, astrocytes impacting metabolic support, and endothelial cells whose pyroptotic death contributes directly to blood-brain barrier disruption. At the molecular level, the priming and activation of the NLRP3 and NLRP1 inflammasomes by diverse triggers, including classical markers like Aβ, environmental neurotoxicants and metabolic stressors, converge on caspase-1 and caspase-8 activation. This cascade culminates in gasdermin D (GSDMD) and gasdermin E (GSDME) pore formation, leading to cellular lysis and the massive release of pro-inflammatory cytokines such as IL-1β and IL-18. Furthermore, this paper explores the emerging and critical concept of PANoptosis, highlighting the intricate crosstalk between pyroptosis, apoptosis, and necroptosis within PANoptosome complexes triggered by mitochondrial dysfunction. We evaluate current and prospective therapeutic strategies, ranging from multi-target natural and traditional herbal remedies to advanced nanomedicine, synthetic small molecules, and epigenetic gene therapies. By integrating insights from blood-based pyroptosis-associated molecular signatures and advanced targeted drug delivery systems, we emphasize the critical need for personalized, multi-targeted approaches to successfully harness pyroptosis modulation in the clinical management and treatment of AD.},
}

Humans
*Pyroptosis/physiology/drug effects
*Alzheimer Disease/pathology/metabolism/therapy
Animals
*Neuroinflammatory Diseases/pathology/metabolism
*Cell Death/physiology
*Molecular Targeted Therapy
Inflammasomes/metabolism

@article {pmid42446992,
year = {2026},
author = {Wong, DYK and Fu, WY and Uhm, H and Jiang, Y and Yip, YCC and Mok, VCT and Kwok, TCY and Ouyang, L and Fu, AKY and Ip, NY},
title = {Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {29},
pages = {e2536489123},
doi = {10.1073/pnas.2536489123},
pmid = {42446992},
issn = {1091-6490},
support = {the Theme-Based Research Scheme [T13-605/18 W] the General Research Fund HKUST16104624 HKUST16102824//the Research Grants Council of Hong Kong/ ; AoE/M-604/16//the Areas of Excellence Scheme of the University Grants Committee/ ; NA//the InnoHK initiative of the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government/ ; Joint Laboratory Funding Scheme [JLFS/M-604/24]//the SIAT-HKUST Joint Laboratory for Brain Science/ ; 2023B1212120004//the Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; ITCPD/17-9//the Innovation and Technology Fund for State Key Laboratory/ ; },
mesh = {*Alzheimer Disease/drug therapy/pathology/metabolism ; Animals ; *Drug Repositioning ; Humans ; Mice ; *Trazodone/pharmacology/therapeutic use ; Microglia/metabolism/drug effects/pathology ; *Interleukin-1 Receptor-Like 1 Protein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Male ; Female ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major isoforms of the ST2 protein encoded by the IL1RL1 (interleukin-1 receptor-like 1) gene-acts as a decoy receptor isoform that interferes with IL-33/ST2 signaling and has been identified as a disease-modifying factor that impairs microglial Aβ clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of commonly used medications in AD patients, followed by validation in model systems, identified trazodone-an antidepressant used to treat major depressive disorder-as a leading negative regulator of sST2. Trazodone primarily suppresses sST2 expression through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology. Furthermore, trazodone reduced neurodegeneration and rescued synaptic deficits in APP/PS1 mice. Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restored the expression of synaptic proteins critical for synaptic integrity and plasticity. Overall, these findings demonstrate that trazodone is a promising repurposing candidate for AD that targets underlying immune dysfunctions and synaptic impairment.},
}

*Alzheimer Disease/drug therapy/pathology/metabolism
Animals
*Drug Repositioning
Humans
Mice
*Trazodone/pharmacology/therapeutic use
Microglia/metabolism/drug effects/pathology
*Interleukin-1 Receptor-Like 1 Protein/metabolism/genetics
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Male
Female
Disease Models, Animal

@article {pmid42447924,
year = {2026},
author = {Nitrini, R and Takada, LT and Brucki, SMD},
title = {The past, present, and future of Alzheimer's disease-part 3: the future.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {6},
pages = {1-10},
doi = {10.1055/s-0046-1824435},
pmid = {42447924},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/prevention & control ; Risk Factors ; Biomarkers ; Forecasting ; },
abstract = {Predicting future advances in science is practically impossible because unexpected discoveries can radically change the march of ongoing processes. Predicting the nearest future may have a slightly greater chance of success. First, the diagnosis of risk factors for Alzheimer's disease (AD), based on the preponderant role of genetics, will be made very early. Diagnosis will be made with biomarkers prior to clinical manifestations. Furthermore, the prevention of AD and of dementia due to AD will be possible with better control of the many risk factors for dementia, healthier lifestyles, multi-target drugs, and genetic therapy. The relationship between AD and aging will be better understood, opening possibilities for intervention in aging itself. As the pathophysiology of AD is not unique, treatment will be individualized, according to the stage and characteristics of the disease. Most clinical trials will have surrogate markers as primary outcomes. Treatments to decrease the velocity or arrest the evolution of mild cognitive impairment (MCI) and mild dementia caused by AD will be available. Additionally, artificial intelligence (AI) will aid in the diagnosis and selection of the best treatments. Access to the new methods for diagnosing and treating AD is currently limited to a small parcel of the population, especially in low- and middle-income countries, because of their high costs. Due to the high prevalence of AD, it is possible these will become less expensive in the future. The possibility of reversing dementia once it has set in will probably have to wait for longer.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/prevention & control
Risk Factors
Biomarkers
Forecasting

@article {pmid42448048,
year = {2026},
author = {Waseem, A and Ghosh, S and Kumari, M and Raza, SS and Verma, S},
title = {Modulation of Inflammasome Biology in Age-Associated Neurodegenerative Diseases: Therapeutic Potential of Endogenous Gasotransmitters and Synthetic Molecules.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103257},
doi = {10.1016/j.arr.2026.103257},
pmid = {42448048},
issn = {1872-9649},
abstract = {Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Endogenous gasotransmitters, including hydrogen sulfide (H2S) and nitric oxide (NO), have emerged as critical modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways that directly or indirectly regulate NLRP3 inflammasome activity. Accumulating evidence suggests that these gaseous mediators exert potent neuroprotective effects by attenuating inflammasome activation, limiting oxidative and nitrosative stress, and preserving neuronal integrity. Despite their therapeutic potential, the pleiotropic and concentration-dependent actions of gasotransmitters pose substantial challenges for precise delivery and controlled bioavailability. However, donors or hybrid molecules, such as peptide conjugates, provide a suitable platform for sustained, controlled release of these gaseous molecules, overcoming their dose-dependent toxicity and facilitating protective biological effects. To date, the most advanced therapeutic strategies have focused on pharmacological inhibition of the NLRP3 inflammasome using synthetic compounds. Preclinical and emerging clinical studies demonstrate that such agents significantly modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms. This review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders, highlights the regulatory roles of endogenous gasotransmitters, and evaluates the therapeutic prospects of synthetic inflammasome-targeting agents for the treatment of neurodegenerative diseases in the aging population.},
}

@article {pmid42448200,
year = {2026},
author = {Murugan, AK},
title = {Oral disease-associated proteins implicated in neuronal disorders: Emerging roles in diagnosis and treatment.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153500},
doi = {10.1016/j.ijbiomac.2026.153500},
pmid = {42448200},
issn = {1879-0003},
abstract = {Oral health plays a crucial role in maintaining cognitive functions, reflecting a complex interplay between the oral cavity and brain health. Emerging evidence indicates that various oral disease-associated protein molecules are implicated in the pathogenesis of diverse neuronal disorders, including neurodegenerative diseases. This review comprehensively summarizes oral disease-related protein molecules implicated in several neuronal disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration, neuroinflammation, dementia, cognitive decline, and brain fog in two different contexts. Firstly, it describes protein molecules under the classical oral disease condition [Aβ42, total-Tau, phosphorylated-Tau, α-synuclein, DJ-1, lactoferrin, MMP-2/8/9, IL-6, IL-1β, TNF-α, CRP, S100A8, S100A9, S100B, RAGE, LCN2, cathepsin B/L, HSP70/90, NfL, CXCL2/8, C3/4, defensins (α and β), and lysozyme]. Secondly, in COVID-19 context [ACE2, TMPRSS2, furin-1, NRP1, spike, T1R, and T2R]. It explores oral proteins implicated in neuronal disorders, highlighting their roles in activating inflammatory pathways, contributing to memory impairment, and mediating taste dysfunction in the context of COVID-19. Furthermore, the review delineates the mechanisms underlying the oral-brain axis, highlighting the roles of systemic inflammation, microbial interactions, and blood-brain barrier dysfunction in mediating these effects. It also highlights the innovative diagnostic potential of oral disease-associated proteins as non-invasive biomarkers for early detection and monitoring of neuronal disorders in both classical and COVID-19 contexts. In addition, the emerging therapeutic significance of these proteins is discussed, emphasizing their potential as molecular targets for the prevention and treatment of neurological diseases. Understanding oral disease-associated protein molecules provides novel insights into early diagnosis and progression of neuronal disorders.},
}

@article {pmid42449057,
year = {2026},
author = {Bukar, AM and Che Mohd Nassir, CMN and Ayuba, M and Manoharan, SD and Usman, AS and Umar, BI and Hein, ZM and Mohd Moklas, MA and Mehat, MZ and Abdul Hamid, H},
title = {Ficus deltoidea Preserves Hippocampal Neuronal Integrity and Redox Balance in Oxidative Stress-Driven Alzheimer's Disease-Like Rat Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42449057},
issn = {1559-1182},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Male ; Rats, Wistar ; *Ficus/chemistry ; *Hippocampus/pathology/drug effects/metabolism ; Disease Models, Animal ; *Neurons/drug effects/metabolism/pathology/ultrastructure ; Oxidation-Reduction/drug effects ; Aluminum Chloride ; *Plant Extracts/pharmacology/therapeutic use ; Galactose ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, with oxidative stress playing a central role in its pathogenesis. Ficus deltoidea (FD), a medicinal plant rich in flavonoids vitexin and isovitexin, possesses potent antioxidant and anti-inflammatory properties, yet its neuroprotective efficacy in AD remains incompletely characterized. This study investigated the protective effects of FD in a D-galactose- and aluminum chloride (AlCl3)-induced oxidative stress-driven AD-like rat model using behavioral, histological, ultrastructural, and biochemical approaches. Fifty-four male Wistar rats were assigned to six groups: control, AD-like model, donepezil (1 mg/kg), and FD-treated groups (50, 100, and 200 mg/kg) for 10 weeks. Anxiety-like behavior and spatial working memory were assessed using the elevated plus maze (EPM) and T-maze tests, respectively. Hippocampal neuronal integrity was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM), while oxidative stress biomarkers (MDA, CAT, T-SOD, CuZn-SOD, and HO-1) were quantified using ELISA. FD treatment, particularly at 200 mg/kg, significantly improved spatial working memory and normalized anxiety-related behavior, with treatment responses approaching those observed in the donepezil-treated group. Histological analyses revealed preservation of pyramidal neurons across CA1, CA2, CA3, and dentate gyrus subregions, while ultrastructural studies demonstrated marked protection of mitochondrial integrity, myelin sheath organization, and smooth endoplasmic reticulum morphology. Biochemically, FD significantly reduced lipid peroxidation and enhanced endogenous antioxidant defenses. In conclusion, FD exerted significant neuroprotective effects characterized by preservation of hippocampal structure, maintenance of neuronal ultrastructure, and restoration of redox homeostasis in an oxidative stress-driven AD-like model. These findings demonstrate that FD mitigates oxidative stress-associated neuronal injury and cognitive impairment in a D-galactose and AlCl3-induced AD-like rat model, supporting its potential as a phytotherapeutic candidate for oxidative stress-related neurodegeneration. However, further studies are required to determine its effects on canonical Alzheimer's disease pathologies, including amyloid and tau abnormalities.},
}

Animals
*Oxidative Stress/drug effects
*Alzheimer Disease/pathology/drug therapy/metabolism
Male
Rats, Wistar
*Ficus/chemistry
*Hippocampus/pathology/drug effects/metabolism
Disease Models, Animal
*Neurons/drug effects/metabolism/pathology/ultrastructure
Oxidation-Reduction/drug effects
Aluminum Chloride
*Plant Extracts/pharmacology/therapeutic use
Galactose
Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology
Rats
Maze Learning/drug effects

@article {pmid42449395,
year = {2026},
author = {Jang, H and Kim, JW and Hwang, JW and Jeong, DW and Ka, J and Kang, DM and Suh, CH and Choi, Y and Oh, M and Kim, JS and Lim, JS and Lee, JH},
title = {Real-world safety and implementation challenges of lecanemab therapy for Alzheimer's disease in South Korea: a single-center experience.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02141-1},
pmid = {42449395},
issn = {1758-9193},
support = {RS-2022-KH125667//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea/ ; 2022-IF-0022//Asan Institute for Life Sciences/ ; },
abstract = {BACKGROUND: Lecanemab, an amyloid-targeting monoclonal antibody, was recently approved for early symptomatic Alzheimer's disease in South Korea. Asians were underrepresented in prior trials, and real-world data from Korea remain scarce, particularly regarding treatment settings, adverse events, and barriers to scalability. We assessed the feasibility and safety of lecanemab among Korean patients in a real-world tertiary hospital.

METHODS: A total of 112 patients initiated lecanemab treatment between December 2024 and October 2025 at Asan Medical Center. Prevalence of infusion-related reactions (IRRs), Amyloid-Related Imaging Abnormalities (ARIA), treatment discontinuation, and factors limiting implementation were evaluated.

RESULTS: Among 112 patients (mean age 71 years; 59% female), IRRs occurred in 41 (37%) and were generally mild or moderate under active surveillance. Among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%). Only 1 patient with isolated ARIA-H presented with transient confusion. Patients with ARIA-E/H were younger, whereas those with ARIA-H were older and more likely to have baseline microhemorrhages. Eleven out of 105 were APOE ε4/ε4 homozygotes, of whom 5 developed ARIA. The rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times-up to 20 weeks 9 months after program initiation.

CONCLUSION: This single-center experience from a tertiary referral hospital in Korea demonstrates that lecanemab treatment was feasible and generally well-tolerated, with manageable adverse events including ARIA and IRRs; however, limited infusion capacity, lack of reimbursement, and patient concentration in tertiary centers highlight the need for referral networks and system-level strategies to improve nationwide accessibility.},
}

@article {pmid42449771,
year = {2026},
author = {Sotoudeh, H and Alizadeh, M},
title = {The Centiloid Scale in Amyloid PET Imaging: Current Role in Alzheimer's Disease Diagnosis, Treatment Planning, and Monitoring During Anti-Amyloid Therapy: A Clinical Perspective.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16131989},
pmid = {42449771},
issn = {2075-4418},
abstract = {Amyloid positron emission tomography (PET) has become a critical tool in the diagnosis and treatment of Alzheimer's disease (AD). The Centiloid (CL) scale, a tracer/scanner-independent, standardized quantification unit introduced in 2015, transforms tracer- and scanner-specific standardized uptake value ratios (SUVRs) into a common metric anchored at 0 CL in young cognitively unimpaired individuals and 100 CL in patients with mild-to-moderate AD. This review synthesizes current evidence on the clinical role of the CL scale across three domains: (1) diagnostic classification, with established thresholds of <10 CL for amyloid negativity and >30 CL for high-certainty amyloid positivity; (2) treatment eligibility, where a 2024 Alzheimer's Association Research Roundtable consensus of global experts recommended a 24-30 CL threshold for initiating lecanemab or donanemab therapy in patients with mild cognitive impairment (MCI) or mild AD dementia; and (3) longitudinal therapy monitoring, in which serial CL measurements provide objective evidence of amyloid clearance. We also review the emerging 'gray zone' (10-30 CL) as a distinct clinical entity with elevated progression risk, the critical role of CL quantification in complementing visual reads in borderline cases, technical limitations, and the future integration of CL in clinical practice. This review also critically addresses the ongoing debate on whether amyloid clearance represents a reliable surrogate for clinical benefit, strategies for managing discordant biomarker findings, and the practical feasibility of serial amyloid PET in routine care. With FDA approval of both lecanemab and donanemab, familiarity with the CL scale as a functional treatment biomarker is increasingly relevant for neuroradiologists and nuclear medicine physicians in the modern AD care pathway. As with all imaging modalities, the CL has physiologic and technical limitations. Although the CL scale was designed to reduce heterogeneity across tracers and scanner platforms, the impact of different commercial quantification software packages on CL output remains incompletely characterized. Consistent use of a single software platform for longitudinal monitoring in individual patients is therefore recommended.},
}

@article {pmid42449980,
year = {2026},
author = {Li, Y and Zhao, H and Wu, J and Hu, Y and Pan, J and Frimpong, AO and Xie, B and Yang, W and Sun, M and Chen, W and Wang, P and Shao, C},
title = {Vitamin K2 Promotes Mitochondrial Structural and Functional Homeostasis to Ameliorate Alzheimer Pathology by Targeting the EGFR-Ras-ERK Signaling Axis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135708},
pmid = {42449980},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Mitochondria/drug effects/metabolism/ultrastructure ; ErbB Receptors/metabolism ; Homeostasis/drug effects ; *Vitamin K 2/pharmacology ; Humans ; *MAP Kinase Signaling System/drug effects ; Drosophila melanogaster ; *ras Proteins/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD[+]/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*Mitochondria/drug effects/metabolism/ultrastructure
ErbB Receptors/metabolism
Homeostasis/drug effects
*Vitamin K 2/pharmacology
Humans
*MAP Kinase Signaling System/drug effects
Drosophila melanogaster
*ras Proteins/metabolism
Signal Transduction/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
Membrane Potential, Mitochondrial/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid42450004,
year = {2026},
author = {Petrov, W and Ślebioda, D and Kozińska, R and Kukla, K and Petrov, P and Sroka, M and Tesyna, J and Puźniak, G and Kudliński, M and Rejda, T and Skowron, I and Chłopaś-Konowałek, A},
title = {Analysis of the Efficacy of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease, Literature Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135733},
pmid = {42450004},
issn = {1422-0067},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Acetylcholinesterase/metabolism ; Rivastigmine/therapeutic use ; },
abstract = {The term 'dementia' encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient's independence. Within this group of disorders, Alzheimer's disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration.},
}

Humans
*Cholinesterase Inhibitors/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Acetylcholinesterase/metabolism
Rivastigmine/therapeutic use

@article {pmid42450155,
year = {2026},
author = {Untiveros, G and St Germain, R and Barrington, B and Kujawa, SA and Prakapenka, AV and Strizzi, L},
title = {Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135885},
pmid = {42450155},
issn = {1422-0067},
mesh = {*Presenilin-1/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Melanoma/metabolism/pathology ; *Tumor Microenvironment ; *Alzheimer Disease/metabolism/pathology ; Mice ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Cell Movement ; },
abstract = {Recent studies report inverse relationships between the incidence of Alzheimer's Disease (AD) and certain malignancies, including melanoma. This has encouraged research into factor(s) in AD that can exert antitumor effects. Presenilin-1 (PS-1) is part of the enzymatic complex that cleaves amyloid precursor protein (APP) into amyloid-beta (Aβ) products that are linked to the neuronal damage seen in AD. PS-1 can also degrade β-catenin and reduce the effectiveness of the "wingless-related integration" (WNT) signaling pathway. Little is known about the relationship between the AD microenvironment, PS-1, and melanoma. We hypothesize that melanoma growth in AD depends on the degree of PS-1-dependent processing of APP into cytotoxic Aβ by melanoma cells. To determine how melanoma reacts to an APP-rich, AD-like microenvironment, PS-1-high (WM1552C) and PS-1-low (C8161) melanoma cells were treated with soluble recombinant human APP (rhAPP). We found that rhAPP treatment significantly reduced cellular activity in WM1552C but not in C8161 cells. Moreover, Aβ products were significantly higher in conditioned media from rhAPP-treated WM1552C compared to controls. Treatment with PS-1 inducing DAPT or PS-1 function inhibiting MRK-560 reversed the effects of rhAPP treatment, respectively in C8161 and WM1552C cells. Furthermore, we found that migration of WM1552C was significantly reduced in the presence of either soluble rhAPP or mouse AD brain tissue, compared to C8161, suggesting that in WM1552C the combination of PS-1 activity and the presence of APP/Aβ in the microenvironment interferes with cell migration. In summary, PS-1 function may predict how melanoma will grow in an APP/Aβ-rich microenvironment, such as AD.},
}

*Presenilin-1/metabolism/genetics
Humans
Animals
*Amyloid beta-Protein Precursor/metabolism/genetics
*Melanoma/metabolism/pathology
*Tumor Microenvironment
*Alzheimer Disease/metabolism/pathology
Mice
Cell Line, Tumor
Amyloid beta-Peptides/metabolism
Cell Movement

@article {pmid42450355,
year = {2026},
author = {Arendash, GW},
title = {Neuronal Microtubules and Radiofrequency Waves: The Quantum Core of Human Consciousness, Memory, and Pathway to Memory Enhancement/Recovery.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136090},
pmid = {42450355},
issn = {1422-0067},
support = {AG025711, 1R43NS090653-01A, and 9R44AG073096-02A1//NIA-designated Florida Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Microtubules/metabolism ; *Memory/physiology/radiation effects ; *Consciousness/physiology ; *Radio Waves ; Animals ; *Neurons/metabolism ; Quantum Theory ; },
abstract = {A unifying theory of both human consciousness and memory is presented that is based on neuronal microtubules (MTs) being central to both, and different populations of pyramidal cells in neocortex and hippocampus being responsible for consciousness or memory. First, two quantum theories of consciousness are presented-the Orchestrated Objective Reduction (Orch OR) theory of Penrose/Hameroff and the Environmental-Induced Decoherence Theory (EID) theory of Neven. A Hybrid (MT/EID) theory is proposed in the context of "consciousness"-dedicated pyramidal cells in Layer V of the cerebral cortex. This MT/EID theory involves the MT vibrations of the Orch OR Theory, along with the continual superposition qubit (SPQ) formation and SPQ entanglement of the EID Theory to collectively induce SPQ formation/entanglement in Layer V of the cerebral cortex. Orch OR's objective reduction (collapse of the waveform) is not included in this Hybrid theory because the system of SPQs themselves continuously collapses due to EID. For memory, it is proposed that Orch OR forms its basis with three specific modifications: (1) presenting "endogenous" radiofrequency (RF) vibrations generated by neuronal microtubules as forming a microtubule/RF wave "vibrational fabric" involving microtubular crystalline water cores, (2) refining Orch OR for memory by proposing SPQ formation for short-term memory and objective reduction of those qubits primarily in "memory-dedicated" pyramidal cells within cortical Layers II/III for long-term memory storage through "Quantum Darwinism" (SPQ/OR), and (3) integrating SPQ/OR with the ability of "externally" applied RF waves at 1 GHz to beneficially influence human memory through microtubule-enhancing mechanisms. It is proposed that a vibrational fabric consisting of MTs, RF waves, and generated photons provides the Photonic/RF-wave quantum coherence necessary for brain memory processing. Strong evidence for beneficial effects of exogenous RF wave treatment on memory is provided by a new bioengineered technology-Transcranial Radiofrequency Wave Treatment (TRFT; also known as TEMT). This evidence is presented in both pre-clinical and clinical studies involving normal and Alzheimer's Disease (AD) transgenic mice, and AD patients bearing memory loss. In support of MT involvement in memory, TRFT would appear to be an ideal non-pharmacologic technology to beneficially modulate the microtubule/RF wave vibrational fabric-an intraneuronal fabric that may be at the deep core of human memory, and thus the key to Alzheimer's Disease memory rescue.},
}

Humans
*Microtubules/metabolism
*Memory/physiology/radiation effects
*Consciousness/physiology
*Radio Waves
Animals
*Neurons/metabolism
Quantum Theory

@article {pmid42440686,
year = {2026},
author = {Feng, X and Bi, S and Shi, C and Chang, Q and Zhang, J and Zhuang, Y},
title = {Comparison of safety of lecanemab and donanemab: a real-world disproportionality analysis using the FDA adverse event reporting system.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1868789},
pmid = {42440686},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab and donanemab are anti-amyloid-β (Aβ) monoclonal antibodies recently approved for the treatment of Alzheimer's disease (AD). Although both agents have demonstrated therapeutic potential, their post-marketing adverse event reporting profiles remain insufficiently characterized and compared in spontaneous reporting systems. This study aimed to systematically compare adverse event signals associated with these two drugs using the FDA Adverse Event Reporting System database, with sex-stratified and sensitivity analyses performed to support the main findings.

METHODS: FAERS reports up to the fourth quarter of 2025 were retrospectively analyzed. Reports in which lecanemab or donanemab was recorded as the primary suspect drug were included. AEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection was performed using four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Sex-stratified analysis, sensitivity analysis after excluding reports involving concomitant medications, and time-to-onset (TTO) analysis based on the Weibull shape parameter model were also conducted. False discovery rate (FDR) correction was applied to analyses involving multiple P values.

RESULTS: A total of 3,640 AE reports were identified, including 2,602 for lecanemab and 1,038 for donanemab. Nervous system disorders was the most frequently reported SOC and the only SOC meeting the positivity criteria across all four algorithms for both drugs. At the PT level, the frequently reported events for both drugs were mainly concentrated in amyloid-related imaging abnormality (ARIA)-related events, including ARIA with oedema/effusion (ARIA-E) and ARIA with microhaemorrhages/haemosiderin deposition (ARIA-H), headache, and infusion-related reactions. The strongest disproportionality reporting signals were mainly observed for ARIA-related preferred terms and cerebral microhaemorrhage. In separate FAERS-based disproportionality analyses, lecanemab showed stronger disproportionality reporting signals for ARIA-H, whereas donanemab showed stronger disproportionality reporting signals for ARIA-E. In addition, drug-specific PT signal distributions differed between the two agents. Several potential novel PT signals were also identified. Sex-stratified analysis suggested differences in the distribution of certain PT signals between female and male reports. Sensitivity analysis supported the stability of most core signals. The median TTO was 46 days for lecanemab and 31 days for donanemab, and Weibull analysis suggested different temporal patterns of AE occurrence.

CONCLUSION: Using four signal detection algorithms, this study compared real-world adverse event reporting profiles associated with lecanemab and donanemab. The two drugs showed both shared and distinct adverse event reporting profiles, particularly in ARIA subtype-related disproportionality signals, drug-specific PT signals, potential novel reporting signals, sex-stratified reporting patterns, and TTO characteristics. These findings provide pharmacovigilance evidence for targeted safety monitoring and hypothesis generation, but should not be interpreted as causal associations or true incidence estimates.},
}

@article {pmid42440728,
year = {2026},
author = {Badesso, S and Espelosín, M and Alonso, C and Montilla, A and Collantes, M and Cuadrado-Tejedor, M and García-Osta, A},
title = {Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70285},
pmid = {42440728},
issn = {2352-8737},
abstract = {INTRODUCTION: Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.

METHODS: The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP[NL-G-F] AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.

RESULTS: PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.

DISCUSSION: These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.},
}

@article {pmid42440762,
year = {2026},
author = {Xing, X and Wang, K and Feng, Y and Wu, C and Jia, L and Li, H and Wen, Z and Tang, Y and Wang, Z and Zhang, X and Li, X and Hua, Y and Zhang, L and Dong, X},
title = {Post-marketing safety of lecanemab: a real-world study based on FAERS database, multicenter cohort and network pharmacology.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1822543},
pmid = {42440762},
issn = {1664-0640},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-beta (Aβ) approved for treating Alzheimer's disease (AD) with mild cognitive impairment or mild dementia. Continuous monitoring of its real-world safety profile remains essential. This study aimed to analyze lecanemab-related adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database and a multicenter cohort, and explored mechanisms via network pharmacology.

METHODS: We conducted an updated disproportionality analysis of FAERS data from 2023 to 2024 to identify disproportionate reporting signals (SDRs). A multicenter retrospective cohort study was performed, including lecanemab users from June 2024 to February 2025. Data were collected from electronic medical records of five tertiary hospitals. AEs were identified and influencing factors of AE occurrence were analyzed. Additionally, a drug-gene interaction network was constructed to explore potential mechanisms.

RESULTS: In the FAERS analysis of 2,764 AEs from 1,389 lecanemab users, 12 of 41 positive SDRs were prioritized, with 75% (9/12) being nervous system disorders, primarily amyloid-related imaging abnormalities (ARIA). In the cohort study, 29.05% (43/148) of patients experienced AEs, with infusion-related reactions being most common. Age was identified as a risk factor for AE occurrence [OR (95% CI): 1.109 (1.011-1.215), P = 0.028], while pre-treatment significantly reduced AE incidence. Gene enrichment analysis suggested potential links between lecanemab-related genes and AEs.

DISCUSSION: This study provides real-world evidence on the risk profile of lecanemab, highlighting the importance of continued safety monitoring. These findings may inform discussions about the risks associated with anti-amyloid treatments and warrant further confirmation in large-scale prospective studies.},
}

@article {pmid42441396,
year = {2026},
author = {Fleisher, AS and Munsie, L and Mancini, M and Cheng, YJ and Guo, J and Nuthall, H and Otero, DS and Kotari, V and Kielbasa, W and Hutton, M and Brys, M and Mergott, DJ and Mintun, M and Hansson, O},
title = {Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12768},
pmid = {42441396},
issn = {1538-3598},
abstract = {IMPORTANCE: Inhibiting O-linked N-acetylglucosaminidase (OGA) is hypothesized to slow accumulation of aggregated, hyperphosphorylated tau and neurofibrillary tangle formation.

OBJECTIVE: To evaluate the efficacy and safety of the potent oral OGA inhibitor ceperognastat in early symptomatic Alzheimer disease (AD).

This double-blind, randomized, placebo-controlled phase 2 study was conducted at 72 sites in 5 countries from September 2021 to August 2024, with a posttreatment observational extension period through May 2025. The primary outcome population comprised participants with early symptomatic AD and biomarker evidence of tau pathology, including low to medium baseline tau levels (excluding individuals with high levels), as measured by positron emission tomography (PET) with flortaucipir F18.

INTERVENTION: Participants were randomized 1:1:1 to receive once-daily, oral ceperognastat at doses of 0.75 mg (n = 110) or 3 mg (n = 108) or placebo (n = 108).

MAIN OUTCOMES AND MEASURES: The primary outcome was change in Integrated AD Rating Scale (iADRS) score. The success criterion was a 60% or greater probability of achieving greater than or equal to 25% slower progression vs placebo using a bayesian probabilistic disease progression model. The 6 secondary outcomes were Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version; Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Clinical Dementia Rating-Sum of Boxes; Mini-Mental State Examination; tau PET; and volumetric magnetic resonance imaging.

RESULTS: Of the 327 randomized participants (mean age, 73.4 years; 201 [61.5%] females), 259 (87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo) with low to medium baseline tau levels were included in the primary outcome population (mean age, 74.3 years; 161 [62.2%] females). In this population, no clinically meaningful benefit vs placebo was observed for the primary end point (iADRS score) at 100 weeks: posterior mean change from baseline was -8.39 with ceperognastat 0.75 mg, -13.27 with ceperognastat 3 mg, and -10.07 with placebo. The disease progression ratio relative to placebo was 0.84 (95% credible interval [CrI], 0.66-1.04) for the ceperognastat 0.75 mg group and 1.32 (CrI, 1.10-1.58) for the ceperognastat 3 mg group, corresponding to 16% less and 32% greater progression, respectively. No benefits were demonstrated for secondary clinical end points. From baseline to 76 weeks, least-squares mean change in standardized uptake value ratio on PET showed a statistically significantly smaller increase (P = .04) vs placebo only for the ceperognastat 3 mg group in the lateral temporal lobe. Volumetric magnetic resonance imaging showed less whole brain volume loss in participants treated with ceperognastat vs placebo (43.2% [ceperognastat 0.75 mg] and 49.5% [ceperognastat 3 mg] less vs placebo; both P < .001). The ceperognastat 3 mg group had more serious (ceperognastat 0.75 mg: n = 13 [12.0%]; ceperognastat 3 mg: n = 29 [26.4%]; placebo: n = 17 [15.7%]) and severe (ceperognastat 0.75 mg: n = 7 [6.5%]; ceperognastat 3 mg: n = 15 [13.6%]; placebo: n = 7 [6.5%]) treatment-emergent adverse events.

CONCLUSIONS AND RELEVANCE: Ceperognastat did not slow disease progression of early symptomatic AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063539.},
}

@article {pmid42441421,
year = {2026},
author = {Wang, L and Cai, Q and Yang, Y and Zhou, Y and Liu, Y and Wu, P and Liu, J and Liu, Y},
title = {A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c05393},
pmid = {42441421},
issn = {1944-8252},
abstract = {A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.},
}

@article {pmid42442404,
year = {2026},
author = {Marsden, M and McLaren, JE and Bevan, RJ and Penn-Ripley, D and Somerville, M and Lauder, SN and Jones, MH and Maros, LB and McGurk, MR and Gallimore, A and Price, DA and Miners, KL and Ladell, K and Siebzehnrubl, FA and Hughes, TR and Humphreys, IR and Clement, M},
title = {Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag043},
pmid = {42442404},
issn = {1460-2156},
support = {//Jane Hodge Foundation/ ; MR/X00922X/1/MRC_/Medical Research Council/United Kingdom ; 207503/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; //Brain Tumour Charity/ ; MR/V000489/1//MRC/ ; MR/S07709/1//MRC/ ; MR/X018318/1//MRC/ ; },
abstract = {Infections have long been implicated as causative factors in Alzheimer's disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.},
}

@article {pmid42442677,
year = {2026},
author = {Shu, XD and Liu, HF and Liao, YQ and Pu, WJ and Zhao, T and Pan, WD and Zhang, N and Li, JY},
title = {Saebias A-G, eudesmane sesquiterpenes from Salvia plebeia with potential for Alzheimer's disease prevention via anti-neuroinflammatory and neuroprotective effects.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {115024},
doi = {10.1016/j.phytochem.2026.115024},
pmid = {42442677},
issn = {1873-3700},
abstract = {Saebias A-G (1-7), seven previously undescribed eudesmane sesquiterpenoids compounds and seventeen known compounds were isolated from Salvia plebeia R.Br. Among them, compound 1 is a unique C16-type eudesmane sesquiterpenoid featuring a 6/6/5-membered scaffold, 2-3 are nor-eudesmane sesquiterpenoids and 5 contains a rare 6/6/3/5 tetracyclic skeleton. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single-crystal X-ray crystallographic and ECD calculation. All compounds were evaluated for their inhibitory effect on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 cells and neuroprotective effect induced by H2O2 in PC12 cells. The results showed that four compounds exhibited significant NO inhibitory effects, with IC50 values ranging from 0.76 to 3.72 μM. Among them, compound 2 showed significant inhibitory effect, which significantly suppressed the production of IL-6, IL-1β, and iNOS in a concentration-dependent manner. The PC12 cells damage induced by H2O2 was attenuated by compounds 2, 10, 11, 13, 15, and 23. Moreover, compounds 2 and 11 delayed H2O2 induced damage, stabilized reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and apoptosis expression levels. Notably, compound 2 exerted dual anti-neuroinflammatory and neuroprotective activities, and its multi-target pharmacological profile makes it a promising candidate for the prevention and treatment of Alzheimer's disease. These studies provide new potential neuroprotective agents for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid42442802,
year = {2026},
author = {Robles, CV and Robles, CV and Revilla, APA and de Jesús Valencia Suárez, V and Santander, MAS},
title = {The Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review.},
journal = {The European journal of neuroscience},
volume = {64},
number = {1},
pages = {e70623},
doi = {10.1111/ejn.70623},
pmid = {42442802},
issn = {1460-9568},
mesh = {Humans ; *Down Syndrome/genetics/complications ; *Alzheimer Disease/genetics/epidemiology ; Amyloid beta-Protein Precursor/genetics ; Dyrk Kinases ; },
abstract = {Down syndrome (DS), the most common chromosomal disorder, is associated with an accelerated aging process, increasing the risk of early-onset Alzheimer's disease. This review examines genetic factors involved in the development of Alzheimer's disease (AD) in people with DS. A systematic search in major databases was conducted, and articles from 2020 to 2025 that met the predefined inclusion criteria were included. The results showed that the prevalence of AD was above 60% in people with DS older than 65 years, the mean age at diagnosis was 53 years, and the mortality occurred around 59 years. The main genetic factor identified was the overexpression of the APP gene, along with other genes such as DYRK1A, RCAN1, SOD1, APOEε4, and genes involved in the immune response, as well as posttranscriptional dysregulation. Diagnosis remains a challenge due to the pre-existent intellectual disability and the atypical clinical presentation of the disease; however, the development of adapted neuropsychological tests, biomarkers, and neuroimaging techniques is expected to facilitate early diagnosis. The connection between both diseases is the result of multiple genetic factors that lead to early onset and accelerated progression of AD. It is essential to achieve timely diagnosis and provide early treatment to improve quality of life of both patients and their caregivers.},
}

Humans
*Down Syndrome/genetics/complications
*Alzheimer Disease/genetics/epidemiology
Amyloid beta-Protein Precursor/genetics
Dyrk Kinases

@article {pmid42443082,
year = {2026},
author = {Li, J and Zhou, B and Yang, Y and Wang, J and Cheng, L and Zhu, C and Zhou, T and Yang, Y and Yin, W and Zhang, Y and Liu, R and Wang, L and Pu, Y and Li, Z},
title = {[Effects of moxibustion at the acupoints of governor vessel on cognitive function and gut microbiota in Alzheimer's disease model mice based on brain-gut axis].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {7},
pages = {1115-1124},
doi = {10.13703/j.0255-2930.20250414-k0003},
pmid = {42443082},
issn = {0255-2930},
mesh = {Animals ; *Moxibustion ; *Alzheimer Disease/therapy/microbiology/psychology/physiopathology/metabolism/genetics ; Mice ; Male ; *Cognition ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; *Acupuncture Points ; *Gastrointestinal Microbiome ; Amyloid beta-Peptides/metabolism/genetics ; Tumor Necrosis Factor-alpha/metabolism/genetics ; Interleukin-6/metabolism/genetics ; *Brain/metabolism/physiopathology ; *Brain-Gut Axis ; Hippocampus/metabolism ; },
abstract = {OBJECTIVE: To observe the effects of moxibustion at the points of governor vessel on cognitive function and gut microbiota in Alzheimer's disease (AD) model mice, and explore the mechanism of moxibustion at governor vessel in treatment of AD.

METHODS: Eighteen APP/PS1 mice were randomly divided into a model group and a moxibustion group, with 9 mice in each group; and the other 9 C57BL/6J mice were collected as a blank group. In the moxibustion group, mild-warm moxibustion was operated at "Baihui" (GV20), suspended moxibustion was at "Fengfu" (GV16) and "Dazhui" (GV14), 20 min in each intervention. Moxibustion was delivered once daily for 2 weeks. The water maze test and the novel object recognition experiment were employed to evaluate the cognitive function of mice, and the contents of β-amyloid 40 (Aβ40), β-amyloid 42 (Aβ42), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus of mice were detected by ELISA, the morphology of hippocampal tissues was observed by HE staining, and the structure of fecal gut microbiota in mice was analyzed by 16S rRNA gene sequencing. The correlation of gut microbiota with the hippocampal Aβ40, Aβ42, TNF-α and IL-6 contents was analyzed.

RESULTS: Compared with the blank group, in the model group, the escape latency was extended (P<0.01), the number of platform crossings decreased (P<0.01), the target quadrant residence time ratio was reduced (P<0.01); the preference index in the novel object experiment increased (P<0.001), and the discrimination coefficient decreased (P<0.001). The contents of Aβ40, Aβ42, TNF-α and IL-6 in the hippocampus rose (P<0.05), the hippocampal neuron structure was imcomplete, with irregular size and arrangement, the neurons were vacuolar and some showed pyknosis and were reduced in number. ACE, Chao1 and Shannon indexes decreased (P<0.001) and the Simpson index rose (P<0.001). The relative abundance of Proteobacteria and Deferribacteres was reduced (P<0.001), that of Lactobacillus and Pasteurella was elevated (P<0.01), while that of Alistipes decreased (P<0.01). Compared with the model group, in the moxibustion group, the escape latency was shortened (P<0.05), the number of crossing the platform increased (P<0.05), and the target quadrant residence time ratio was higher (P<0.05); the preference index decreased (P<0.001), and the discrimination coefficient increased (P<0.001). The contents of Aβ40, Aβ42, TNF-α and IL-6 in the hippocampus decreased (P<0.01). Hippocampal tissue injury was attenuated. ACE, Chao1 and Shannon indexes increased (P<0.05), and Simpson index decreased (P<0.05). The relative abundance of Proteobacteria and Deferribacteres increased (P<0.05), that of Lactobacillus decreased (P<0.001). The correlation was presented between gut microbiota and the contents of hippocampal Aβ40, Aβ42, TNF-α and IL-6 in the moxibustion group.

CONCLUSION: Moxibustion at governor vessel points can improve cognitive function in AD mice, reduce Aβ accumulation, inhibit neuroinflammation, which may be related to the recovery of gut microbiota homeostasis.},
}

Animals
*Moxibustion
*Alzheimer Disease/therapy/microbiology/psychology/physiopathology/metabolism/genetics
Mice
Male
*Cognition
Humans
Disease Models, Animal
Mice, Inbred C57BL
*Acupuncture Points
*Gastrointestinal Microbiome
Amyloid beta-Peptides/metabolism/genetics
Tumor Necrosis Factor-alpha/metabolism/genetics
Interleukin-6/metabolism/genetics
*Brain/metabolism/physiopathology
*Brain-Gut Axis
Hippocampus/metabolism

@article {pmid42443567,
year = {2026},
author = {Muratori, BG and Caetano, CR and da Veiga, IET and Soliani, AG and E Silva, SMS and Gava, JP and Ceridório, LF and Caselli, L and Ureshino, RP and Prado, CM and Cerutti, SM},
title = {Standardized Extract of Ginkgo biloba L. Reverses Memory Impairment in Older Female Mice with Basal Forebrain Cholinergic Dysfunction.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42443567},
issn = {1573-6903},
mesh = {Animals ; Female ; Ginkgo biloba ; *Plant Extracts/therapeutic use/pharmacology ; *Memory Disorders/drug therapy/metabolism ; Ginkgo Extract ; Amyloid beta-Peptides/metabolism ; Mice ; Aging/drug effects ; tau Proteins/metabolism ; Vesicular Acetylcholine Transport Proteins/genetics/metabolism ; *Prosencephalon/drug effects/metabolism ; Mice, Inbred C57BL ; Peptide Fragments ; },
abstract = {Aging induces neurochemical changes, particularly in the dentate gyrus (DG), that impair memory. In late-onset Alzheimer's disease (LOAD), neuronal loss in regions like the entorhinal cortex (EC) and hippocampus proper (HP), along with amyloid-β (Aβ) plaques, tau tangles, and reduced cholinergic signaling, accelerates cognitive decline. Building on our group's previous findings of cognitive benefits and neuroprotection from Ginkgo biloba L. leaf extract (EGb), and considering the limited success of current therapies, EGb has emerged as a promising multi-target strategy for reversing memory impairments. This study evaluates the effects of chronic EGb treatment on memory, anxiety-like behaviors, and motor activity in older female wild-type and VAChT knockdown KD[HET] and KD[HOM] mice, which show 45% and 65% reductions in VAChT expression, respectively. We assessed the impact of EGb on Aβ1-42 peptide and phosphorylated tau (pTauT231) by quantifying Aβ IR[+] and pTau IR[+] cells in the dCA1, dCA3, and dDG, via immunohistochemistry. Results showed that aging led to short- and long-term memory deficits, which were exacerbated in the VAChT KD[HOM] mice. However, EGb treatment reversed these deficits in a dose-dependent manner by modulating Aβ and pTau-IR[+] cells in the dCA1, and dDG regions. In vitro, EGb significantly inhibited Aβ aggregation through interactions with Aβ and the POPC monolayer. These findings suggest that EGb may provide a promising therapeutic strategy for AD, improving cognition and offering neuroprotection by targeting key neuropathological features like Aβ plaques and phosphorylated tau.},
}

Animals
Female
Ginkgo biloba
*Plant Extracts/therapeutic use/pharmacology
*Memory Disorders/drug therapy/metabolism
Ginkgo Extract
Amyloid beta-Peptides/metabolism
Mice
Aging/drug effects
tau Proteins/metabolism
Vesicular Acetylcholine Transport Proteins/genetics/metabolism
*Prosencephalon/drug effects/metabolism
Mice, Inbred C57BL
Peptide Fragments

@article {pmid42443606,
year = {2026},
author = {Akbari, V and Bahramikia, S},
title = {Tau physiology and pathology: impacts on cellular structures and neurodegenerative diseases.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42443606},
issn = {1568-5608},
abstract = {This review explores the crucial roles of the tau protein in neuronal integrity and its dysregulation in neurodegenerative diseases (NDs), particularly tauopathies. Key features include abnormal tau phosphorylation, leading to insoluble aggregates and neuronal dysfunction. Various therapeutic strategies, such as reducing tau phosphorylation, inhibiting aggregation, and enhancing clearance through autophagy and immunotherapies, are discussed. Promising candidates such as anle138b and methylene blue display efficacy in preclinical models. The interplay between tau and Aβ pathology is also highlighted, emphasizing the complexity of therapeutic approaches. A thorough understanding of tau functions is essential for developing targeted treatments to combat tau-related neurotoxicity and advance therapies for Alzheimer's disease (AD). This article examines the dual role of tau in physiology and pathology, highlighting its effects at both the cellular and subcellular levels. These findings underscore the critical importance of the tau protein in preventing NDs and suggest that a deeper understanding of its functions could improve treatment strategies for tau-related disorders.},
}

@article {pmid42444486,
year = {2026},
author = {Li, Q and Fan, B and Xiao, Y and Zhang, Z and Zhao, S and Liao, B and Zeng, J and Shan, X and Ye, H and Wen, Y and Zhang, L and Guo, H and Xiao, F and Zhu, H},
title = {Branched-chain amino acids and gut microbiota: coregulation and impact on neurological function via the gut-brain axis.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2698204},
doi = {10.1080/19490976.2026.2698204},
pmid = {42444486},
issn = {1949-0984},
mesh = {*Amino Acids, Branched-Chain/metabolism ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism/physiology ; *Nervous System Diseases/metabolism/microbiology ; *Gastrointestinal Tract/microbiology/metabolism ; },
abstract = {Diseases that cause neurological dysfunction, such as Parkinson's disease (PD), Alzheimer's disease (AD), and maple syrup urine disease (MSUD), among others, are characterized by complex and multifaceted etiologies. There is growing evidence that branched-chain amino acids (BCAAs), regulated by the gut microbiota, play a critical role in the development of the central nervous system (CNS) disorders. This review focuses on the potential role of branched-chain amino acid metabolism in regulating brain function and gut microbiota. First, we summarize the current understanding of BCAAs, encompassing their biochemical metabolism, function, and systemic metabolic mechanisms. Subsequently, we delve into the mechanisms through which the gut microbiota regulates branched-chain amino acid metabolism, along with its mechanistic insights and recent evidence of its impact on neurological disorders. Finally, we discuss future research directions and challenges regarding gut BCAAs metabolism as a potential treatment for brain and gastrointestinal dysfunction.},
}

*Amino Acids, Branched-Chain/metabolism
Humans
*Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism/physiology
*Nervous System Diseases/metabolism/microbiology
*Gastrointestinal Tract/microbiology/metabolism

@article {pmid42429089,
year = {2026},
author = {Zhang, Z and Li, D and Liu, J and Lu, L and Cai, W and Yu, G},
title = {[Mechanism of Bushen Yijing Formula in improving cognitive function in Alzheimer's disease model mice].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-12},
doi = {10.3724/zdxbyxb-2025-0747},
pmid = {42429089},
issn = {1008-9292},
abstract = {OBJECTIVES: To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking.

METHODS: Twelve amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into normal control, model, and BSYJF groups. The treated group received daily intragastric administration of BSYJF for 12 consecutive weeks. Cognitive function and hippocampal amyloid β-protein (Aβ) deposition were assessed using behavioral tests and immunohisto-chemistry. Hippocampal tissues were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and qPCR was used to validate expression changes of core target genes.

RESULTS: BSYJF treatment improved cognitive function and reduced hippocampal Aβ deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-κB. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF downregulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings.

CONCLUSIONS: Transcriptomics, bioinformatics analysis, and animal experiments suggest that BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.},
}

@article {pmid42429504,
year = {2026},
author = {Lu, K and Lu, Y and Tang, R and Dong, X and Zhuang, P and Gao, Y and Cheng, M and Wang, Y and Wang, Y},
title = {Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460879},
doi = {10.1177/13872877261460879},
pmid = {42429504},
issn = {1875-8908},
abstract = {The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.},
}

@article {pmid42430015,
year = {2026},
author = {Khodaei, M and Bidabad, B and Shiri, ME and Sedaghat, MK},
title = {Ricci Flow-Based Approach for Early Diagnosis of Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {3},
pages = {},
pmid = {42430015},
issn = {1559-0089},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; *Hippocampus/diagnostic imaging/pathology ; Female ; Aged ; Male ; Discriminant Analysis ; *Image Interpretation, Computer-Assisted/methods ; Aged, 80 and over ; Imaging, Three-Dimensional/methods ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is increasingly important due to its rising prevalence and significant impact on individuals, families, and healthcare systems. Hippocampal atrophy is a well-established and significant biomarker for AD. Advanced techniques like MRI imaging and surface parameterization have shown considerable promise in improving the accuracy and speed of AD diagnosis. This study aims to utilize the Ricci flow method to map the 3D hippocampal surface to a 2D sphere and extract relevant features for early AD detection. The process involves several key steps: inputting an MRI scan and preprocessing to isolate the hippocampal surface, applying the Ricci flow to map this surface to a sphere, constructing a feature vector using Linear Discriminant Analysis (LDA) and Kernel LDA, and employing various classifiers to diagnose AD, with model evaluation based on the ADNI dataset. Experimental results reveal that combining Ricci flow-based feature extraction with Kernel LDA significantly improves diagnostic accuracy. The model achieves classification accuracies of 97.28% (NC/AD), 96.14% (NC/EMCI), 96.45% (NC/MCI), 94.83% (EMCI/LMCI), 95.84% (MCI/AD), and 95.37% (LMCI/AD). Additionally, it attains 93.65% and 92.30% accuracy in three-way and four-way classification tasks, respectively. These results outperform most reviewed studies and are comparable to others. This research highlights the potential of merging advanced 3D imaging techniques with mathematical models to enhance diagnostic precision, emphasizing the critical role of early detection in the effective treatment and management of Alzheimer's disease.},
}

*Alzheimer Disease/diagnostic imaging
Humans
*Magnetic Resonance Imaging/methods
Early Diagnosis
*Hippocampus/diagnostic imaging/pathology
Female
Aged
Male
Discriminant Analysis
*Image Interpretation, Computer-Assisted/methods
Aged, 80 and over
Imaging, Three-Dimensional/methods

@article {pmid42431348,
year = {2026},
author = {Ma, Q and Ding, Z and Wang, R and Jin, J and Wang, H and Li, Y and Liu, Z and Wang, X and Yin, T},
title = {40 Hz-rTMS modulates spike-LFP coupling and improves cognitive function in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115909},
doi = {10.1016/j.expneurol.2026.115909},
pmid = {42431348},
issn = {1090-2430},
abstract = {OBJECTIVE: Spike-local field potential (LFP) coupling plays a pivotal role in mediating cross-scale neural communication. Although abnormal coupling has been reported in Alzheimer's disease (AD) models in vitro, in vivo evidence remains lacking. This study aimed to characterize in vivo spike-LFP coupling in 5XFAD mice and investigate whether 40 Hz repetitive transcranial magnetic stimulation (rTMS) can ameliorate related deficits.

METHODS: We performed chronic in vivo electrophysiological recordings of spikes and LFPs were performed in the hippocampal dentate gyrus (DG) via. Phase-locking and coherence analysis were employed to quantify spike-LFP coupling. Cognitive function was evaluated using the Y-maze, novel object recognition, and Morris water maze tasks. The correlation between spike-LFP coupling and cognitive performance was analyzed by the Spearman method.

RESULTS: In wild-type (WT) sham mice, DG spikes exhibited tightly confined phase preferences (θ oscillation: 108°-126°; high γ (Hγ) oscillation: 198°-216°). In contrast, 5XFAD mice displayed severely dispersed spike-phase distributions and reduced coupling intensity, with mean vector length decreasing by 19.90% (spike-θ) and 23.8% (spike-Hγ) compared with that in WT-sham controls. Following 14 consecutive days of 40 Hz rTMS intervention, 5XFAD mice exhibited significant increases in mean vector length (θ: +39.44%; Hγ: +31.47%) and normalized spike-LFP phase distributions. Notably, rTMS treatment also markedly rescued learning, memory, and cognitive flexibility in 5XFAD mice. Spike-LFP coupling strength was significantly correlated with learning and memory performance.

CONCLUSION: These preliminary findings suggest that 40 Hz rTMS modulates pathological spike-LFP coupling in 5XFAD mice, laying the groundwork for therapeutic exploration.},
}

@article {pmid42431472,
year = {2026},
author = {Kurz, CI and Tegethoff, P and Gelz, J and Gkempelsi, I and Hufnagel, A and Neziraj, F and Schuhbauer, P and Rahn, H and Boeck, M and Keidel, LF and Perneczky, R},
title = {The DECISION Study: Protocol for the Development and Internal Validation of a Multimodal Decision-Making Capacity Framework.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112417},
doi = {10.1016/j.jclinepi.2026.112417},
pmid = {42431472},
issn = {1878-5921},
abstract = {BACKGROUND: Decision-making capacity (DMC) is a prerequisite for valid informed consent, as well as being a key methodological requirement in clinical and epidemiological research. For individuals with neurocognitive disorders, DMC assessment is frequently based on subjective clinical judgement, with limited standardization and significant variability across settings. Current instruments are resource-intensive and not sufficiently adapted for stage-specific or real-world applications.

OBJECTIVE: To develop and internally validate a structured multimodal framework for assessing decision-making capacity in individuals across the Alzheimer's disease continuum.

METHODS: We propose a modular assessment framework that operationalizes the core domains of decision-making capacity: understanding, appreciation, reasoning and expression of choice. This is complemented by neuropsychological profiling, informant-based measures and structured decision scenarios. Internal validation will be performed against established functional reference standards, including the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), while the Clinical Dementia Rating (CDR) will be used for disease characterization only. Primary analyses focus on feasibility, reliability, and criterion validity. Biomarkers and neuroimaging measures are examined as exploratory contextual correlates of decisional vulnerability and are not used to define decision-making capacity. The co-design approach thus integrates both patient and caregiver perspectives as well as clinician and expert input, with focus group interviews providing a complementary, structured format to capture interdisciplinary professional perspectives.

RESULTS: The protocol is designed to generate evidence regarding feasibility, reliability, and criterion validity of a multimodal DMC assessment framework. It provides standardized scoring and quantifiable outputs, as well as a basis for stage-sensitive interpretation. Exploratory analyses will further evaluate associations between functional decision-making capacity and markers of neurodegenerative disease burden. This methodological framework provides a standardized, reproducible approach to assessing decision-making capacity in cognitively vulnerable populations.

CONCLUSIONS: Developed within the German legal framework, it integrates cognitive, functional and contextual dimensions to support more transparent and quantifiable capacity assessment. Following external validation, the framework may inform future clinical studies, observational research, and ethically robust consent procedures in cognitively impaired populations.},
}

@article {pmid42432671,
year = {2026},
author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N},
title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04551-7},
pmid = {42432671},
issn = {1477-3155},
abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.},
}

@article {pmid42433215,
year = {2026},
author = {Cai, L and Zhao, X and Liao, C and Liu, Q and Hu, S and Huang, M},
title = {Efficacy and predictors of cognitive stimulation therapy combined with pharmacotherapy for mild-to-moderate Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1840039},
pmid = {42433215},
issn = {1664-0640},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with progressive cognitive decline, functional impairment, and reduced quality of life. Although pharmacological treatments such as cholinesterase inhibitors and memantine are commonly used, their clinical benefits remain limited and heterogeneous. Cognitive stimulation therapy (CST) may provide additional benefits when combined with standard pharmacotherapy. This randomized controlled trial (RCT) aimed to evaluate the clinical efficacy of modified CST combined with standard drug therapy on cognitive function, activities of daily living, and quality of life in patients with mild-to-moderate AD and to explore key predictors of CST efficacy using a multivariate regression model.

METHODS: This evaluator-blinded randomized controlled trial enrolled 80 patients with mild-to-moderate Alzheimer's disease (AD), who were randomly assigned in a 1:1 ratio to either the modified CST plus standard pharmacotherapy group (study group, n = 40) or the standard pharmacotherapy-alone group (control group, n = 40).The modified CST program comprised 14 weekly 45-minute sessions. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score from baseline to post-intervention. Secondary measures included the Activities of Daily Living (ADL) scale and the Quality of Life in Alzheimer's disease (QOL-AD) questionnaire. Data were analyzed using an intention-to-treat (ITT) approach. Independent predictors of treatment efficacy were identified using a two-stage screening strategy (univariate screening and stepwise regression).

RESULTS: A total of 75 patients completed the study, and 80 were included in the ITT analysis. After 14 weeks of intervention, baseline-adjusted ANCOVA showed that the study group had significantly better post-intervention ADAS-Cog scores than the control group. The adjusted mean difference in ADAS-Cog score was -3.28 points (95% CI: -3.72 to -2.83; P < 0.001), favoring the study group. Significant baseline-adjusted between-group differences were also observed for ADL (adjusted mean difference = -4.93, 95% CI: -8.39 to -1.47; P = 0.006) and QOL-AD (adjusted mean difference = 2.69, 95% CI: 1.01 to 4.37; P = 0.002), both favoring the study group. Higher years of education (β = -0.54, P < 0.001), regular physical activity (β = -0.28, P = 0.003), higher baseline Mini-Mental State Examination (MMSE) scores (β = -0.22, P = 0.001), and active hobbies (β = -0.20, P = 0.002) were significant independent predictors of CST efficacy.

DISCUSSION: Modified CST combined with medication significantly delays cognitive decline and improves QOL-AD in patients with mild-to-moderate AD. Educational attainment, lifestyle factors, and cognitive reserve are key determinants of CST efficacy. Relevant institutions should develop targeted enhancement protocols for patients with lower educational levels or insufficient cognitive reserves when implementing CST.

TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier ChiCTR2600118654, https://www.chictr.org.cn.},
}

@article {pmid42435043,
year = {2026},
author = {Dabas, A and Yadav, P and Singh, R},
title = {Exploring thiazole conjugates as cholinesterase inhibitors for Alzheimer's disease treatment.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17568919.2026.2699679},
pmid = {42435043},
issn = {1756-8927},
abstract = {Alzheimer's Disease (AD), a major global health concern, is marked by memory loss and cognitive decline, especially in the elderly. Cholinergic hypothesis is one of the leading hypotheses toward the treatment of AD, prompting the development of cholinesterase (ChE) inhibitors. Acetylcholinesterase (AChE) remains a vital therapeutic target due to its role in enhancing acetylcholine levels and neural function. The natural products, synthetic analogs, and hybrid molecules have been evaluated as inhibitors of ChEs. Recent studies highlight thiazole-fused heterocyclic scaffolds and their derivatives as promising ChE inhibitors with neuroprotective potential. This article covers the synthesis of conjugates of thiazole with piperazine, benzimidazole, pyrazole, and other heterocyclic compounds, along with their potential as ChE inhibitors. This article will be useful to medicinal chemists and pharmaceutical industries to design and synthesize library of thiazole conjugates.},
}

@article {pmid42435703,
year = {2026},
author = {Ghose, A and Paidesetty, SK and Prusty, SK and Satapathy, BS and Panda, PK and Pakeeraiah, K and Mishra, A and Dandela, R},
title = {Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110242},
doi = {10.1016/j.bioorg.2026.110242},
pmid = {42435703},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.},
}

@article {pmid42436821,
year = {2026},
author = {Shan, G and Zhang, Y and Ding, AA},
title = {Statistical inference for saved time based on disease progression curves in Alzheimer's disease research.},
journal = {Contemporary clinical trials communications},
volume = {52},
number = {},
pages = {101664},
pmid = {42436821},
issn = {2451-8654},
abstract = {Saved time is an easy interpretation metric that provides information to patients on how long a new treatment can delay the disease progression in time as compared to the placebo. The frequently used projection approach for saved time estimation utilizes limited information from the available data. To address that limitation, the area above the disease progression curve was proposed to estimate saved time by using more information from data. However, it is a challenge to derive the closed-form statistical inference (e.g., confidence interval of saved time) as area above the curve is quadratic relative to visit time and saved time based on the curves is nonlinearly related to the area above the curve. In this article, we derived the closed-form variance of saved time based on the area above curve approach by using Taylor expansion. We then compared the performance of the closed-form method and the existing simulation-based method to construct the confidence interval for saved time based on the area above curve approach with regard to coverage probability and interval width under various scenarios. The simulation results indicate that the proposed closed-form method has similar performance as compared to the existing method, while the closed-form method can be computationally easy in practice without additional simulations in the existing method. Data from the completed phase 2 donanemab trial were used to illustrate the application of the proposed method.},
}

@article {pmid42437499,
year = {2026},
author = {Brown, CA and Robinson, JL and Das, SR and McGrew, E and Suh, E and Van Deerlin, VM and Irwin, DJ and Nasrallah, IM and Mechanic-Hamilton, D and Yushkevich, PA and Wolk, DA and Lee, EB},
title = {Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13058},
pmid = {42437499},
issn = {1538-3598},
abstract = {IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration.

OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels.

This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included.

EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years.

MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness.

RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (β = -0.50 [95% CI, -0.62 to -0.37]; t = -7.96 and P < .001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls.

CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.},
}

@article {pmid42438228,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kim, SY and Oh, TW and Ji, M and Nam, JW and Baek, M and Park, JH and Shin, WH and Kim, HJ and Choi, B and Paik, MJ and Kim, H},
title = {Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70345},
doi = {10.1002/ddr.70345},
pmid = {42438228},
issn = {1098-2299},
support = {RS-2024-00347522//National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice ; Brain/metabolism/drug effects ; Male ; *Naphthoquinones/pharmacology/chemistry/therapeutic use ; Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Peptide Fragments/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Scopolamine ; Madin Darby Canine Kidney Cells ; *Neuroprotective Agents/pharmacology ; Cognitive Enhancement ; },
abstract = {Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.},
}

Animals
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Mice
Brain/metabolism/drug effects
Male
*Naphthoquinones/pharmacology/chemistry/therapeutic use
Humans
*Cognitive Dysfunction/drug therapy/metabolism
Peptide Fragments/metabolism
Alzheimer Disease/drug therapy/metabolism
Scopolamine
Madin Darby Canine Kidney Cells
*Neuroprotective Agents/pharmacology
Cognitive Enhancement

@article {pmid42438861,
year = {2026},
author = {Liu, X and Lin, T and Jiang, Y and Luo, S and Chen, S and Chai, Y and Yang, Z and Wei, Y and Wang, H and Li, X and Xiang, YT and Sha, F and Tang, J},
title = {Antidepressant use and dementia, cognitive measures, and neuroimaging outcomes: A population-based cohort study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e225},
doi = {10.1017/S0033291726104942},
pmid = {42438861},
issn = {1469-8978},
support = {82404371//National Natural Science Foundation of China/ ; 72304267//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Antidepressive Agents/therapeutic use/adverse effects ; Female ; Male ; *Dementia/epidemiology/diagnostic imaging ; Aged ; Neuroimaging ; Prospective Studies ; *Cognition/drug effects ; United Kingdom/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Cohort Studies ; UK Biobank ; },
abstract = {BACKGROUND: Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.

METHODS: We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006-2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n = 57,330) and structural brain imaging (n = 42,276) were examined as intermediate outcomes.

RESULTS: Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4 years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36-1.60), AD (1.53, 1.36-1.73), and VD (1.44, 1.23-1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.

CONCLUSIONS: Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.},
}

Humans
*Antidepressive Agents/therapeutic use/adverse effects
Female
Male
*Dementia/epidemiology/diagnostic imaging
Aged
Neuroimaging
Prospective Studies
*Cognition/drug effects
United Kingdom/epidemiology
Middle Aged
Magnetic Resonance Imaging
Brain/diagnostic imaging
Cohort Studies
UK Biobank

@article {pmid42439335,
year = {2026},
author = {Singh, S and Singh, S and Khandelwal, V and Bharti, U and Singh, PK},
title = {Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455874260702045636},
pmid = {42439335},
issn = {1996-3181},
abstract = {Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.},
}

@article {pmid42439669,
year = {2026},
author = {Robert, J},
title = {What Are the Potential Therapeutic Benefits of Targeting Blood-Borne Lipoproteins in the Treatment of Alzheimer's Disease?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131191},
pmid = {42439669},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/therapy ; *Lipoproteins/blood/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Lipoproteins, HDL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the deposition of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles, and cerebrovascular dysfunction. Evidence suggests that blood-borne lipoproteins play a role in the disease's pathophysiology by influencing the cerebrovasculature and amyloid metabolism. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) can contribute to oxidative stress, endothelial dysfunction, vascular dysfunction, and the accumulation of amyloidogenic peptides, thereby exacerbating neurodegeneration. The role of lipoprotein(a) (Lp(a)) remains unclear, whereas high-density lipoprotein (HDL) is recognized for its cerebroprotective properties, including anti-inflammatory and vasoreactive functions. These properties help to maintain neuronal homeostasis and facilitate the clearance of Aβ from the brain. This review summarizes the current evidence regarding the role of lipoproteins in AD and discusses how therapeutic strategies targeting lipoprotein pathways, such as lipid-lowering agents and HDL mimetics developed for cardiovascular diseases, may benefit patients with AD.},
}

Humans
*Alzheimer Disease/drug therapy/blood/therapy
*Lipoproteins/blood/metabolism
Animals
Amyloid beta-Peptides/metabolism
Lipoproteins, HDL

@article {pmid42440180,
year = {2026},
author = {Mohamadpour, M and Amandadi, M and Javan, M and Hosseinkhani, S},
title = {A Combination of Artemisinin, N-acetylcysteine, Resveratrol, and Hesperidin Ameliorates Hippocampal Damage and Pathological Features in an Experimental Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42440180},
issn = {1573-6903},
mesh = {Animals ; *Resveratrol/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Hippocampus/drug effects/pathology/metabolism ; *Hesperidin/therapeutic use/administration & dosage ; *Acetylcysteine/therapeutic use/administration & dosage ; Male ; *Artemisinins/therapeutic use/administration & dosage ; *Neuroprotective Agents/therapeutic use/administration & dosage ; Rats ; Disease Models, Animal ; Drug Therapy, Combination ; Streptozocin ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and pathological accumulation of amyloid-β and tau proteins. This study investigated the potential neuroprotective effects of a combined treatment consisting of artemisinin, N-acetylcysteine, resveratrol, and hesperidin in a streptozotocin (STZ)-induced intracerebroventricular (ICV) rat model of AD. Twenty 8-week-old rats were divided into four groups: control, SHAM, STZ-ICV, and STZ-ICV receiving oral administration of the compound combination for 30 days. Cognitive performance was evaluated using the Morris water maze and passive avoidance tests. Neurodegenerative and molecular changes were assessed through Western blot analysis of phosphorylated tau, amyloid-β-related markers, and apoptosis- and inflammation-associated proteins. Histological analyses included Nissl staining and immunofluorescence for amyloid deposition and caspase-3 expression. Results demonstrated that STZ-ICV administration induced significant cognitive impairment, neuronal loss, and increased amyloid-β and phosphorylated tau levels. Treatment with the combined compounds partially improved behavioral performance and was associated with reductions in amyloid-β deposition, tau phosphorylation, and caspase-3 expression, along with improved neuronal preservation in the hippocampus. These findings suggest that the combined administration of artemisinin, N-acetylcysteine, resveratrol, and hesperidin exerts multi-target neuroprotective effects in an experimental AD model, potentially through modulation of oxidative stress, neuroinflammation, and apoptotic pathways. However, further studies are required to evaluate pharmacokinetics, safety, and translational relevance before clinical application.},
}

Animals
*Resveratrol/therapeutic use/administration & dosage
*Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism
*Hippocampus/drug effects/pathology/metabolism
*Hesperidin/therapeutic use/administration & dosage
*Acetylcysteine/therapeutic use/administration & dosage
Male
*Artemisinins/therapeutic use/administration & dosage
*Neuroprotective Agents/therapeutic use/administration & dosage
Rats
Disease Models, Animal
Drug Therapy, Combination
Streptozocin
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Maze Learning/drug effects
Rats, Sprague-Dawley

@article {pmid42440193,
year = {2026},
author = {Adiniaev, Y and Omar, M and Daniel, O and Timor, TM and Barash, Y and Brook, OR and Klang, E and Gorenshtein, A},
title = {Generative large language models in the clinical management of Alzheimer's disease and mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42440193},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Cognitive Dysfunction/therapy/diagnosis ; *Large Language Models ; Generative Artificial Intelligence ; },
abstract = {BACKGROUND: Dementia affects over 55 million people worldwide. Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD). Clinical management requires integrating uncertain evidence from neuropsychological testing, neuroimaging, and biomarkers. Large language models (LLMs) also generate probabilistic outputs, but whether they can reliably support diagnostic, therapeutic, or educational tasks in AD and MCI has not been systematically examined.

METHODS: We searched PubMed, Scopus, and PubMed Central (January 2023 to April 2026) for studies evaluating generative LLMs on clinical tasks in Alzheimer's disease (AD) or mild cognitive impairment (MCI). Risk of bias was assessed using QUADAS-AI and AXIS. Narrative synthesis followed the SWiM guideline.

PROSPERO: CRD420261372436.

RESULTS: Eleven studies were included: diagnosis (n = 3), treatment guidance (n = 2), and patient/caregiver education (n = 8); two studies contributed to multiple domains. Diagnostic models achieved high internal accuracy (0.94-0.97) but declined on external validation; three-way classification accuracy dropped approximately 7% points, and MMSE-prediction R² collapsed from 0.90 to 0.25 on an external dataset. Treatment guidance approached but did not match structured clinical guidelines. Educational outputs were rated moderate to high quality but lacked source attribution and exceeded recommended reading levels; retrieval augmentation improved usability without improving accuracy. Hallucination was quantified in only 2 of 11 studies, and no study evaluated prospective clinical use.

CONCLUSIONS: Current evidence does not support the use of LLMs for diagnosis, treatment selection, or patient education in AD/MCI without clinician oversight. These findings reflect the specific model versions, prompting strategies, and evaluation conditions in place at the time of each study, and are further limited by small heterogeneous evaluations, sparse hallucination measurement, and absence of prospective clinical validation.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
*Cognitive Dysfunction/therapy/diagnosis
*Large Language Models
Generative Artificial Intelligence

@article {pmid42440589,
year = {2026},
author = {Huang, X and Xu, G and Zhou, Y and Wang, D and Ai, L and Liu, H and Fan, A and Wang, L and Zhang, P},
title = {P2-engineered exosomes encapsulating curcumin alleviate cognitive decline in AD-like mice by improving microglia-related neuropathology.},
journal = {Materials today. Bio},
volume = {39},
number = {},
pages = {103388},
doi = {10.1016/j.mtbio.2026.103388},
pmid = {42440589},
issn = {2590-0064},
abstract = {Natural exosomes, as drug carriers, can deliver anti-inflammatory agents across the blood-brain barrier (BBB) to lesion sites in the brain, thereby demonstrating immense potential in the treatment of brain inflammation-related diseases. However, the application of natural exosomes is constrained by their poor targeting ability. Herein, we report a novel drug delivery system (P2-Exo-Cur) constructed by engineering exosomes to display the P2 peptide on their surface, thereby enabling targeted delivery of curcumin to microglia. Our results revealed that P2-Exo-Cur possesses a nanoscale membrane structure and can efficiently deliver curcumin to microglia both in vitro and in vivo. This technology provides a microglia-targeted delivery approach for anti-inflammatory agents such as curcumin, while overcoming the undesirable off-target effects that limit their efficacy. Furthermore, treatment of lipopolysaccharide (LPS)-induced inflammatory BV2 cell models with P2-Exo-Cur significantly suppressed the polarization of BV2 cells toward the M1 phenotype, as well as the secretion of pro-inflammatory cytokines. Finally, we also validated the excellent therapeutic potential of this technology in the 5xFAD mouse model. In conclusion, in this study, we for the first time constructed engineered exosomes that can specifically bind to the NCAM protein on microglia to achieve precise delivery of curcumin by expressing the P2 peptide on their surface, exerting beneficial effects in AD treatment without causing significant adverse effects. This strategy may offer a non-invasive and innovative therapeutic method for the management of brain inflammation-related diseases.},
}

@article {pmid42440665,
year = {2026},
author = {Han, J and Sun, Y and Song, Y and Wu, Y and Wang, X},
title = {The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1843537},
doi = {10.3389/fphar.2026.1843537},
pmid = {42440665},
issn = {1663-9812},
abstract = {BACKGROUND: Ligustilide (LIG), a natural phthalide compound mainly isolated from Angelica sinensis and Ligusticum chuanxiong, has attracted increasing attention because of its diverse pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects. Emerging studies suggest that LIG may have therapeutic relevance in central nervous system (CNS) disorders.

PURPOSE: This review systematically summarizes the pharmacological effects, molecular mechanisms, pharmacokinetic characteristics, metabolism, safety profile, and therapeutic potential of LIG in CNS disorders.

METHODS: Relevant studies published up to 26 October 2025 were retrieved from PubMed, Web of Science, and Scopus using keywords related to ligustilide, central nervous system disorders, pharmacokinetics, metabolism, and toxicity. After removing duplicate records and excluding reviews, editorials, and irrelevant articles, 55 eligible original studies were included in this review.

RESULTS: Current evidence indicates that LIG exerts neuroprotective effects in multiple CNS disorders, including ischemic stroke, cerebral ischemia-reperfusion injury, vascular dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and anxiety disorders. Its mechanisms mainly involve modulation of PI3K/Akt, MAPK, NF-κB, Nrf2/ARE, AMPK, and other signaling pathways, leading to reduced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. In addition, available studies suggest that LIG can cross the blood-brain barrier and shows relatively favorable safety in preclinical models.

CONCLUSION: LIG demonstrates broad neuroprotective potential in preclinical studies and may represent a promising candidate for CNS disease intervention. However, its poor chemical stability, low oral bioavailability, limited toxicity evaluation, and lack of clinical evidence remain major challenges for translational application. Further studies are required to optimize delivery strategies and validate its efficacy and safety in clinical settings.},
}

@article {pmid42427890,
year = {2026},
author = {Lin, F and Teng, Y},
title = {Magnolol mitigates neuroinflammation via NF-κB/IL-6/IL-1β pathways in AlCl3-induced Alzheimer's disease: insights from in-vivo and in-silico investigations.},
journal = {3 Biotech},
volume = {16},
number = {8},
pages = {314},
pmid = {42427890},
issn = {2190-572X},
abstract = {The neuroprotective effectiveness of natural substances against neuroinflammatory pathways linked to Alzheimer's disease (AD) is still not well understood. In this study, we used both in vivo and in silico methods to assess the therapeutic potential of magnolol at dosages of 25 and 50 mg/kg body weight in a rat model of AD produced by aluminium chloride (AlCl3). Significant cognitive impairments, elevated levels of malondialdehyde (MDA), and increased expression of important neuroinflammatory mediators, including nuclear factor kappa-B (NF-κB), interleukin (IL-6), and interleukin-1β (IL-1β), were all brought on by exposure to AlCl3. Magnolol treatment markedly reduced the levels of pro-inflammatory cytokines, lactate dehydrogenase (LDH), and nitric oxide (NO), improved cognitive function, and strengthened antioxidant defence systems as shown by increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. Histopathological examination further validated Magnolol's neuroprotective properties, showing decreased neuronal degeneration. Magnolol has substantial binding affinities for NF-κB, IL-6, and IL-1β, according to molecular docking and dynamic modelling studies, indicating that it can directly influence neuroinflammatory signalling pathways. Overall, these results show that magnolol has important neuroprotective effects by reducing oxidative stress and inhibiting important inflammatory mediators, underscoring its potential as an effective treatment option for AD.},
}

@article {pmid42428551,
year = {2026},
author = {Li, W and Yu, X and Guo, C and Huang, Y and Wei, Z and Liu, Y and Wang, JZ and Liu, R and Ji, W and Duan, Q and Wang, J and Wang, G and Wang, X},
title = {Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.},
journal = {MedComm},
volume = {7},
number = {7},
pages = {e70863},
pmid = {42428551},
issn = {2688-2663},
abstract = {Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.},
}

@article {pmid42426112,
year = {2026},
author = {Kim, Y and Choudhary, A and Kim, H and Teale, P and McConnell, B and Al Borno, M},
title = {Comparing vibrotactile stimulation to combined visual and auditory stimulation for 40 Hz gamma entrainment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60911-1},
pmid = {42426112},
issn = {2045-2322},
abstract = {There is significant interest in combined visual and auditory stimulation to entrain 40 Hz gamma oscillations for the treatment of Alzheimer's disease and other neurological conditions such as stroke and insomnia. In this work, we compared another sensory modality-vibrotactile stimulation delivered with a glove-to visual and auditory stimulation in 15 healthy participants in terms of electroencephalogram (EEG) responses and subjective experience. We found that vibrotactile stimulation from the glove could evoke 40 Hz EEG responses in the central, frontal and, to a lesser extent, occipital cortices. We also observed distinct patterns of functional connectivity between the two stimulation modalities. Participants preferred the vibrotactile stimulation over the visual and auditory stimulation. Our study supports future investigations on vibrotactile stimulation for the treatment of neurological conditions.},
}

@article {pmid42426158,
year = {2026},
author = {Vöglein, J and Levin, J and Stögmann, E and Haass, C and Höglinger, GU and Frölich, L and Jessen, F},
title = {Attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab: results from a multicenter survey in Europe.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42426158},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/genetics ; Female ; Male ; Aged ; Europe ; Surveys and Questionnaires ; Cross-Sectional Studies ; Middle Aged ; Aged, 80 and over ; Memory ; },
abstract = {Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer's disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer's Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer's disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8-86.2) and general EU approval (91.8%, 95% CI 87.9-94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2-66.9; approval: 76.5%, 95% CI 71.1-81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p < 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.},
}

Humans
*Alzheimer Disease/drug therapy/psychology/genetics
Female
Male
Aged
Europe
Surveys and Questionnaires
Cross-Sectional Studies
Middle Aged
Aged, 80 and over
Memory

@article {pmid42426326,
year = {2026},
author = {Wu, Q and Fan, D and Ren, J and Xing, Y and Chen, Z and Jin, H and Lu, Y and Wang, X and Zheng, H},
title = {SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42426326},
issn = {1559-1182},
mesh = {*Sumoylation/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy ; },
abstract = {Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.},
}

*Sumoylation/physiology
*Neurodegenerative Diseases/metabolism/pathology
Humans
*Mitochondria/metabolism/pathology
Animals
Mitophagy

@article {pmid42427159,
year = {2026},
author = {Bevins, EA and Léger, GC and Herman, MA and Ringman, JM and Roy, S and Shtrahman, M and Pa, J and Feldman, HH},
title = {Safety considerations of gene-based therapies for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71515},
pmid = {42427159},
issn = {1552-5279},
support = {//Epstein Family Alzheimer's Research Collaboration (EFARC)/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/genetics ; *Genetic Therapy/adverse effects/methods ; Gene Therapy Agents ; Animals ; Dependovirus/genetics ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Gene-based therapies show increasing promise for the treatment of neurologic disease. In 2016, nusinersen, an RNA-based therapy, was approved for children with spinal muscular atrophy (SMA). Over 200 clinical trials have utilized gene therapy approaches for a host of neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD).[1] Delivering gene-based therapies to the central nervous system (CNS) has raised safety concerns. As clinical trials utilizing gene therapy paradigms are undertaken and as approved therapies translate into clinics, a better understanding of safety issues and monitoring parameters is needed. We describe current therapeutic approaches for AD using gene-based therapies such as adeno-associated virus gene therapy and RNA interference by antisense oligonucleotides (ASOs) and undertake a review of medical safety considerations for existing AD gene therapy trials. We identify challenges in analyzing medical safety data currently available and provide guidelines for making this information more accessible and interpretable for the future.},
}

Humans
*Alzheimer Disease/therapy/genetics
*Genetic Therapy/adverse effects/methods
Gene Therapy Agents
Animals
Dependovirus/genetics
Oligonucleotides, Antisense/therapeutic use

@article {pmid42427416,
year = {2026},
author = {Cvek, B},
title = {Comment on "Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases" by Q. Jiang, M. Jiang, Y. Lv, X. Zhang, S. Wang and J. Zhao, RSC Adv., 2025, 15, 36344.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42427416},
issn = {2046-2069},
abstract = {The referenced article reviews the purported anti-inflammatory properties of disulfiram, an anti-alcohol drug also known as Antabuse. However, the anti-inflammatory properties of disulfiram should be considered alongside a wealth of scientific research demonstrating its potential to treat various conditions, including cancers, Alzheimer's disease, sepsis, tuberculosis, blindness and heart conditions. I argue that almost all these results are unreliable using basic chemical knowledge. Most importantly, disulfiram has never been shown to be an active molecule in vivo. The authors of the referenced article did not address this fact at all. Testing disulfiram in vitro yields misleading and dangerous pseudoscientific "results", suggesting that it could be a potential treatment for an ever-growing list of diseases.},
}

@article {pmid42427668,
year = {2026},
author = {Pallerla, AV and Lucido, CC and Saito, K and Nolt, GL and Arbones-Mainar, JM and Funnell, JL and Satish, D and Smith, LM and Stephens, IO and Goulding, D and MacLean, SM and Olmsted, SM and Adreon, D and Hernandez, G and Golden, LR and Persohn, S and Macauley, SL and Territo, PR and Morganti, J and Johnson, LA},
title = {Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734793},
pmid = {42427668},
issn = {2692-8205},
abstract = {Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population.},
}

@article {pmid42422549,
year = {2026},
author = {Ruesga Mundo, S},
title = {Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer's disease and related dementias.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1841647},
pmid = {42422549},
issn = {2813-3919},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes-including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors-indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.

HYPOTHESIS: The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle "Signal → Plasticity → Stable State" and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological-Neurological-Endocrine-Immunological (PNEI) network, and (5) interoceptive-neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.

DEVELOPMENT OF THE HYPOTHESIS: Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010-2025), the model specifies how gene-environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property-distinct from allostatic load-that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.

TESTABLE PREDICTIONS: This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.

CONCLUSION: The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer's disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.},
}

@article {pmid42423023,
year = {2026},
author = {Kim, S and Oda, H and Oyama, R and Makishi, R and Bade, S and Bade, S and Ally, I and Iijima, Y and Gibo, Y and Minami, K and Fukuzawa, F and Sanji, S and Inamine, K and Kishi, H and Huh, S and Tanifuji, T and Nagahiro, M and Watanabe, N},
title = {Efficacy, safety and policy implications of anti-amyloid monoclonal antibodies for Alzheimer's disease: protocol for a living systematic review and meta-analysis.},
journal = {BJPsych open},
volume = {12},
number = {4},
pages = {e182},
doi = {10.1192/bjo.2026.12044},
pmid = {42423023},
issn = {2056-4724},
abstract = {BACKGROUND: Dementia affects approximately 6-13% of adults aged 65 years and older, with Alzheimer's disease accounting for most cases. Established symptomatic therapies, including acetylcholinesterase inhibitors and memantine, provide limited benefit and do not modify disease progression. Multiple monoclonal antibodies (mABs) targeting different amyloid-β species have been developed as potential disease-modifying therapies; because some agents have entered clinical use whereas others remain investigational, a continuously updated synthesis of their efficacy and safety is needed.

AIMS: To evaluate the efficacy and safety of all anti-amyloid mABs for adults with Alzheimer's disease, using a living systematic review and meta-analysis.

METHOD: We will conduct a living systematic review and meta-analysis in accordance with the Cochrane Handbook, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 and the PRISMA extension for living systematic reviews. Randomised controlled trials comparing any approved or investigational anti-amyloid mAB with placebo, standard care or active comparators will be included. Searches of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be updated every 6 months. Meta-analyses will be conducted separately for each antibody molecule using random-effects models. Critical outcomes include global clinical change and disease severity, cognitive abilities, functional ability and dependency, and safety (serious adverse events, treatment discontinuation and amyloid-related imaging abnormalities). Important outcomes include neuropsychiatric symptoms, quality of life and health system outcomes. Certainty of evidence will be assessed using the methodology Grading of Recommendations, Assessment, Development and Evaluation.

RESULTS: This article describes a protocol; therefore, no review findings are available at this stage.

CONCLUSIONS: This living systematic review will provide an up-to-date synthesis of the benefits and harms of anti-amyloid monoclonal antibodies to inform clinical decision-making and health-system planning in Alzheimer's disease.},
}

@article {pmid42423667,
year = {2026},
author = {Huang, Q and Zuo, Y and Xie, Y and Liu, Z and Wang, L and Xu, H and Yu, M and Liu, C},
title = {A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6bm00624h},
pmid = {42423667},
issn = {2047-4849},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.},
}

@article {pmid42423809,
year = {2026},
author = {Yousef, AI and El-Twab, SMA and Khadrawy, SM and Abdel-Moneim, A and Khalil, RG},
title = {Polydatin inhibits hippocampal neurodegeneration in diabetic rats via modulation of oxidative stress and NF-kB/COX-2/IL-6 inflammatory pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42423809},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Glucosides/pharmacology/therapeutic use ; *Stilbenes/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Rats ; Cyclooxygenase 2/metabolism ; *Diabetes Mellitus, Experimental/metabolism/drug therapy ; *NF-kappa B/metabolism ; Interleukin-6/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Impaired insulin function and persistent hyperglycemia damage the brain of diabetics and raise the risk of Alzheimer's disease (AD). Although polydatin (PLD) possesses promising biological effects, no major study has yet explored its anti-neurodegenerative efficacy in the hippocampus. This study therefore aims to investigate the probable protective effects of PLD against hippocampal neurodegeneration in diabetic rats, as well as explore its in-silico inhibitory activity against two key enzymes implicated in the progression of AD. Experimental diabetes was induced in male albino rats then PLD was administered orally to the diabetic rats (50 mg/kg b.wt.) daily for four weeks. In silico molecular docking was used to predict the interactions of PLD against BACE1 and AChE. PLD treatment significantly improved diabetic parameters, lowering blood glucose and raising serum insulin. Excitingly, PLD markedly alleviated oxidative stress by reducing lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses (elevated GPx activity and GSH content) in the hippocampus of diabetic rats. PLD also suppressed neuroinflammation by down-regulating NF-κB, COX-2, and IL-6 mRNA expression. Furthermore, PLD significantly elevated the protein level of IDE while lowered Aβ1-42 level. In silico, PLD revealed potent binding affinity for BACE1 (-8.6 Kcal/mol) and AChE (-10.5 Kcal/mol), interacting with key residues, indicating its inhibition potential. Overall, PLD effectively reduced neurodegeneration in the hippocampus of diabetic rats via inhibiting oxidative stress, inflammation, and Aβ1-42 accumulation. PLD may act as a promising multi-target anti-neurodegenerative candidate, capable of simultaneously modulating multiple pathways and more experimental validation are needed in the future.},
}

Animals
*Oxidative Stress/drug effects
*Glucosides/pharmacology/therapeutic use
*Stilbenes/pharmacology/therapeutic use
*Hippocampus/drug effects/metabolism/pathology
Male
Rats
Cyclooxygenase 2/metabolism
*Diabetes Mellitus, Experimental/metabolism/drug therapy
*NF-kappa B/metabolism
Interleukin-6/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Molecular Docking Simulation
*Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid42424238,
year = {2026},
author = {Tshimbombu, TN and Thurmann, KE and Decourt, B and Nyalundja, AD and Shardow, SB and Amoako, ME and Iragi, GM and Mwambali, JA and Sabbagh, MN},
title = {Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000553506},
pmid = {42424238},
issn = {1660-2862},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.

SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.

KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.},
}

@article {pmid42424917,
year = {2026},
author = {Lapmanee, S and Thonapan, N and Sriwong, S and Bhubhanil, S and Wongchitrat, P and Charoenphon, N and Ngernsutivorakul, T and Hooncharoen, K and Bunwatcharaphansakun, P and Khongkow, M and Namdee, K},
title = {RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119724},
doi = {10.1016/j.biopha.2026.119724},
pmid = {42424917},
issn = {1950-6007},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut-brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery.

METHODS: Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood-brain barrier (BBB) via integrin αvβ3-mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro. Anti-inflammatory and antioxidant effects were assessed in Aβ/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated.

RESULTS: CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-α, p < 0.001) and intracellular reactive oxygen species (p < 0.001). In vivo, CBD/LNP-RGD improved cognitive performance comparable to Donepezil (p < 0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced Aβ and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin.

CONCLUSIONS: CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut-brain axis highlights its potential as a disease-modifying strategy for Alzheimer's disease.},
}

@article {pmid42425064,
year = {2026},
author = {Rudman, MD and Ulrich, JD and Holtzman, DM},
title = {Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.},
journal = {Cell},
volume = {189},
number = {14},
pages = {4193-4224},
doi = {10.1016/j.cell.2026.06.006},
pmid = {42425064},
issn = {1097-4172},
mesh = {*Alzheimer Disease/therapy/pathology/drug therapy/metabolism/immunology ; Humans ; Animals ; Apolipoproteins E/metabolism/genetics ; Plaque, Amyloid/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.},
}

*Alzheimer Disease/therapy/pathology/drug therapy/metabolism/immunology
Humans
Animals
Apolipoproteins E/metabolism/genetics
Plaque, Amyloid/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42425385,
year = {2026},
author = {Thakkar, A and Mote, C and Gadade, A and Dighe, V and Kaur, G and Vora, A},
title = {Longifolene mitigates amyloid beta induced neurotoxicity by acting on PI3K/AKT/NFκB pathway: Comprehensive in vitro, in vivo pharmacokinetics and pharmacodynamic studies for Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179119},
doi = {10.1016/j.ejphar.2026.179119},
pmid = {42425385},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a multifactorial disease characterized with deposition of Amyloid-β peptide leading to oxidative stress and neuroinflammation. Terpenes are a broad class of natural compounds known to possess anti-oxidant and anti-inflammatory effects. Longifolene (LNF), a major constituent of pine resin is a non -polar sesquiterpene possessing promising anti-oxidant and anti-inflammatory activity. Oxidative stress and neuroinflammation are pathological drivers of AD. The current work is focused on evaluating the neuroprotective potential of LNF using in vitro cell line-based and in vivo animal-based model for AD. Pre-treatment with LNF at 1, 10 and 100 μM displayed significant neuroprotective potential in Aβ1-42 induced neurotoxicity in SH-SY5Y cell-line. Additionally, 0.5 and 1μM of LNF significantly prevented ROS generation, mitochondrial dysfunction and apoptosis in SH-SY5Y cell-line. Pharmacokinetic studies in rats showed that LNF achieved the therapeutic concentrations in brain. Further, in pharmacodynamic studies, 20 days pre-treatment and 30 days post-treatment with LNF at 10, 50 and 100 mg/kg resulted in dose-dependent improvements in behavioral, biochemical and histopathological parameters in Aβ1-42 induced AD in rats. Functional assays demonstrated that LNF brought about significant reduction in levels of AChE, TNF-α and IL-6 levels and elevation in BDNF in the rat brain. Histopathological examination of the cortex and hippocampus showed that LNF at doses of 50 and 100 mg/kg markedly attenuated neuronal swelling and cortical atrophic changes, while preserving the pyramidal layer thickness in the hippocampus. Protein expression studies using western blot analysis showed that LNF displays anti-AD activity by acting on PI3K/AKT/NFκB pathway. These findings highlight LNF as a potential neuroprotective agent for AD intervention.},
}

@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}

*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy
Humans
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Models, Biological
Positron-Emission Tomography

@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}

@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {2},
pages = {e70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Chemokines/metabolism/immunology
Animals
Female
Male
Sex Factors
Signal Transduction
Virus Diseases/immunology
Neuroinflammatory Diseases/immunology
COVID-19/immunology
Receptors, Chemokine/metabolism
Brain/immunology/metabolism
Sex Characteristics

@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}

@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}

@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid42418270,
year = {2026},
author = {Caselli, RJ and Geldmacher, DS and Schilling, TB},
title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.},
journal = {The neurologist},
volume = {31},
number = {4},
pages = {129-135},
pmid = {42418270},
issn = {2331-2637},
support = {//Eli Lilly and Company, Indianapolis, IN/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.

REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.

CONCLUSION: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies, Monoclonal/therapeutic use
Plaque, Amyloid/drug therapy
Animals

@article {pmid42418504,
year = {2026},
author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J},
title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71655},
pmid = {42418504},
issn = {1552-5279},
support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; },
abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.

METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.

RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion.

DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
*Homeostasis/drug effects
Female
Male
*B-Lymphocyte Subsets/drug effects/immunology
Aged
*Antibodies, Monoclonal/therapeutic use/pharmacology
*B-Lymphocytes/drug effects/immunology
Leukocytes, Mononuclear/drug effects

@article {pmid42419633,
year = {2026},
author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M},
title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107527},
doi = {10.1016/j.nbd.2026.107527},
pmid = {42419633},
issn = {1095-953X},
abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.},
}

@article {pmid42420256,
year = {2026},
author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ},
title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04188-y},
pmid = {42420256},
issn = {2158-3188},
support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.},
}

@article {pmid42420546,
year = {2026},
author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S},
title = {Stylopine as multi-target anti-Alzheimer agent.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61364-2},
pmid = {42420546},
issn = {2045-2322},
support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.},
}

@article {pmid42421820,
year = {2026},
author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM},
title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70291},
pmid = {42421820},
issn = {2352-8737},
abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).

METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg.

RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.

CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.},
}

@article {pmid42422111,
year = {2026},
author = {Wang, J and Fu, X and Liu, J and Yang, Y},
title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1842455},
pmid = {42422111},
issn = {1663-4365},
abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.},
}

@article {pmid42422228,
year = {2026},
author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA},
title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70422},
pmid = {42422228},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.

METHODS: Eligible volunteers had retinal scans 48 hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.

RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.

DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.},
}

@article {pmid42422260,
year = {2026},
author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M},
title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {199-206},
pmid = {42422260},
issn = {2667-2421},
abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.},
}

@article {pmid42411221,
year = {2026},
author = {Sharma, A and Kaur, A and Khan, J and Pandey, H},
title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249455878260609100548},
pmid = {42411221},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.},
}

@article {pmid42411440,
year = {2026},
author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y},
title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {47145},
doi = {10.31083/JIN47145},
pmid = {42411440},
issn = {0219-6352},
mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.

METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.

RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.

CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.},
}

*Transcranial Direct Current Stimulation
Humans
*Nervous System Diseases/therapy
*Randomized Controlled Trials as Topic
Meta-Analysis as Topic
Systematic Reviews as Topic
*Outcome Assessment, Health Care/statistics & numerical data

@article {pmid42411945,
year = {2026},
author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N},
title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000738},
pmid = {42411945},
issn = {1546-4156},
support = {//Teikoku Seiyaku/ ; },
abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.

METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5 mg patches with donepezil hydrochloride 5 mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.

RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).

CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.},
}

@article {pmid42412004,
year = {2026},
author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M},
title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462927},
doi = {10.1177/13872877261462927},
pmid = {42412004},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.},
}

@article {pmid42412302,
year = {2026},
author = {Zhang, C and Ma, Y and Shi, Z and He, X and Hu, J and Chen, S and Wu, H and Tian, M and Yan, C and Xing, M and He, L},
title = {Study on the Effects and Mechanisms of Resveratrol in Improving Cognitive Impairment in Aβ1-42-Induced Alzheimer's Disease Model Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42412302},
issn = {1557-1904},
mesh = {Animals ; *Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Male ; Autophagy/drug effects ; Mice, Inbred C57BL ; *Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.},
}

Animals
*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/chemically induced/drug therapy/metabolism
*Amyloid beta-Peptides/toxicity
Mice
*Peptide Fragments/toxicity
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
Disease Models, Animal
Male
Autophagy/drug effects
Mice, Inbred C57BL
*Antioxidants/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid42412614,
year = {2026},
author = {Duan, W and Xing, Y and Liu, W},
title = {Protocol for generating multiplexed prime-edited monoclonal cell lines in porcine fetal fibroblasts.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104691},
doi = {10.1016/j.xpro.2026.104691},
pmid = {42412614},
issn = {2666-1667},
abstract = {Porcine fetal fibroblasts (PFFs) serve as standard donor cells for generating cloned pigs, and prime editing (PE) enables precise genome modification. Here, we describe a protocol for generating multiplexed prime-edited monoclonal cell lines in PFFs. We describe steps for pegRNA/ngRNA design and screening, plasmid electroporation, nocodazole treatment, puromycin selection, and monoclonal isolation and genotyping. Although demonstrated by introducing three Alzheimer's disease-associated pathogenic mutations, the pipeline can be readily adapted to multiplex PE of other endogenous loci in porcine cells. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].},
}

@article {pmid42412645,
year = {2025},
author = {Hidasi, Z and Fullajtár, M},
title = {[Special aspects of the treatment of Alzheimer's disease (Anti-amyloid therapies and management of BPSD)].},
journal = {Psychiatria Hungarica : A Magyar Pszichiatriai Tarsasag tudomanyos folyoirata},
volume = {40},
number = {3-4},
pages = {274-281},
pmid = {42412645},
issn = {0237-7896},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/therapy ; *Amyloid beta-Peptides/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Immunization, Passive ; },
abstract = {Due to its diverse symptomatology, Alzheimer's disease requires a complex therapeutic approach. Among the disease-modifying pharmacotherapeutic options, significant progress has recently been made in the field of anti-amyloid antibody therapies. These are generally costly procedures in which passive immunization targets various components of the beta-amyloid cascade. The individual agents differ significantly in terms of efficacy and potential side effects/complications. Considering the questionable degree of cognitive effectiveness, and the associated risks, the exact evaluation of the practical applicability of these agents is currently not possible; long-term data analysis is needed. The symptom cluster of behavioral and psychological symptoms of dementia (BPSD) is in itself complex, encompassing a wide range of clinical phenomena. These symptoms, which frequently occur in everyday patient care and often have multifactorial origins and pathomechanisms, require a complex therapeutic approach. The therapeutic benefit of pharmacological treatments applicable to specific symptom clusters is often difficult to determine due to potential side effects; therefore, individualized treatment supplemented with non-pharmacological methods is warranted. Keywords: Alzheimer's disease; anti-amyloid therapies; behavioral and psychological symptoms of dementia (BPSD).},
}

Humans
*Alzheimer Disease/drug therapy/psychology/therapy
*Amyloid beta-Peptides/immunology
Antibodies, Monoclonal, Humanized/therapeutic use
Immunization, Passive

@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}

@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}

@article {pmid42403709,
year = {2026},
author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G},
title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839516},
pmid = {42403709},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.},
}

@article {pmid42403869,
year = {2026},
author = {Tuleubayeva, A},
title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e110287},
pmid = {42403869},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.},
}

@article {pmid42404289,
year = {2026},
author = {Larson, ST and Susman, JL},
title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {603347},
pmid = {42404289},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.},
}

@article {pmid42404421,
year = {2025},
author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M},
title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {583-594},
pmid = {42404421},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.

METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal Aβ injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after Aβ injection. The possible molecular changes in the hippocampus following Aβ injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.

RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by Aβ in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the Aβ group, which was concurrent with behavioral alterations.

CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.},
}

@article {pmid42404899,
year = {2026},
author = {Oh, SJ and Shin, OS and Hur, JY},
title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839357},
pmid = {42404899},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; },
abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.},
}

Humans
*Alzheimer Disease/immunology/pathology/virology
Animals
*Virus Diseases/immunology
Brain/immunology/virology/pathology
Host-Pathogen Interactions/immunology
SARS-CoV-2/immunology

@article {pmid42406171,
year = {2026},
author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L},
title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42406171},
issn = {1573-6903},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.},
}

Animals
*Toll-Like Receptor 4/metabolism
Male
*Vorinostat/therapeutic use/pharmacology
Female
*NF-kappa B/metabolism
Mice, Inbred C57BL
Mice
*Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced
Lipopolysaccharides
*Sex Characteristics
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Signal Transduction/drug effects
Microglia/drug effects/metabolism
Neuroprotective Agents/therapeutic use/pharmacology
Disease Models, Animal
Hippocampus/drug effects/metabolism
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid42406553,
year = {2026},
author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J},
title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76480},
doi = {10.1002/advs.76480},
pmid = {42406553},
issn = {2198-3844},
support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; },
abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.},
}

@article {pmid42406649,
year = {2026},
author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06099},
pmid = {42406649},
issn = {1944-8252},
abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.},
}

@article {pmid42410071,
year = {2026},
author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y},
title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42410071},
issn = {1573-6903},
support = {2024CXPT029, 2025CXPT011//Key R&D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.},
}

Animals
Lipopolysaccharides/toxicity
Mice, Transgenic
*tau Proteins/genetics/metabolism
Female
*Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control
Mice
Microglia/drug effects/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Alzheimer Disease/drug therapy/metabolism
Hippocampus/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid42410083,
year = {2026},
author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R},
title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42410083},
issn = {1476-5578},
abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.},
}

@article {pmid42410183,
year = {2026},
author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V},
title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42410183},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration & dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Alzheimer Disease/metabolism/drug therapy/pathology
*Phosphatidylinositol 3-Kinases/metabolism
Mice, Transgenic
Disease Models, Animal
*TOR Serine-Threonine Kinases/metabolism
*Lithium/pharmacology/administration & dosage/therapeutic use
Signal Transduction/drug effects
Protein Interaction Maps/drug effects
Proteomics
Mice

@article {pmid42395049,
year = {2026},
author = {Hofmann, A and Perneczky, R},
title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70367},
pmid = {42395049},
issn = {2352-8729},
abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.},
}